Human Gene Module / Chromosome 7 / BRAF

BRAFv-raf murine sarcoma viral oncogene homolog B

SFARI Gene Score
1S
High Confidence, Syndromic Criteria 1.1, Syndromic
Autism Reports / Total Reports
7 / 20
Rare Variants / Common Variants
50 / 0
EAGLE Score
13.05
Strong Learn More
Aliases
BRAF, B-RAF1,  BRAF1,  NS7,  RAFB1
Associated Syndromes
Cardiofaciocutaneous syndrome, Cardiofaciocutaneous syndrome, DD, epilepsy/seizur
Chromosome Band
7q34
Associated Disorders
ID, ASD
Genetic Category
Rare Single Gene Mutation, Syndromic
Relevance to Autism

De novo missense variants in the BRAF gene have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the SPARK cohort (Wang et al., 2020). Single-molecular molecular inversion probe (smMIP) sequencing of 125 genes in over 16,000 cases with neurodevelopmental disorders and comparison of the mutation burden to non-psychiatric controls from ExAC in Wang et al., 2020 identified BRAF as a gene showing a significant burden of ultra-rare (MAF < 0.01%) missense variants with CADD scores equal to or greater than 30 (Mis30 variants) with a false discovery rate (FDR) less than 5%; a total of 11 Mis30 variants in BRAF from 14 individuals were used in this analysis, with 5 of these individuals coming from cohorts with a primary diagnosis of ASD. Patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found in two reports to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Molecular Function

This gene encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene are associated with cardiofaciocutaneous syndrome (CFC) [MIM:115150], a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have also been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to BRAF (20 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome Rodriguez-Viciana P , et al. (2006) No -
2 Highly Cited Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome Niihori T , et al. (2006) No -
3 Support Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with Costello syndrome Nava C , et al. (2007) No Autistic features
4 Recent Recommendation Autism traits in the RASopathies Adviento B , et al. (2013) No Autistic features
5 Primary Behavioral profile in RASopathies Alfieri P , et al. (2014) No Autistic features, ID
6 Support Synaptic, transcriptional and chromatin genes disrupted in autism De Rubeis S , et al. (2014) Yes -
7 Support Large-scale discovery of novel genetic causes of developmental disorders Deciphering Developmental Disorders Study (2014) No -
8 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
9 Support - Okuzono S et al. (2019) No ASD
10 Support Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population Monies D , et al. (2019) No -
11 Recent Recommendation Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders Wang T et al. (2020) Yes ID
12 Support - Hiraide T et al. (2021) Yes -
13 Support - Chen JS et al. (2021) No ASD
14 Support - Mahjani B et al. (2021) Yes -
15 Support - Wang Q et al. (2022) No -
16 Support - Hu C et al. (2022) Yes -
17 Support - Zhou X et al. (2022) Yes -
18 Support - Tamam Khalaf et al. (2024) No ADHD, epilepsy/seizures
19 Support - Shenglan Li et al. (2024) No -
20 Support - Ruohao Wu et al. (2024) Yes -
Rare Variants   (50)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
- - translocation De novo - - 38593811 Shenglan Li et al. (2024)
- - missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.739T>G p.Phe247Val missense_variant De novo - - 28135719 et al. (2017)
c.770A>G p.Gln257Arg missense_variant De novo - - 28135719 et al. (2017)
c.1591T>A p.Trp531Arg missense_variant De novo - - 28135719 et al. (2017)
c.1595G>A p.Cys532Tyr missense_variant De novo - - 28135719 et al. (2017)
c.1738A>G p.Asn580Asp missense_variant De novo - - 28135719 et al. (2017)
c.1802A>T p.Lys601Ile missense_variant De novo - - 28135719 et al. (2017)
n.719+1G>T p.? splice_site_variant Unknown - - 33004838 Wang T et al. (2020)
c.35C>T p.Ala12Val missense_variant De novo - - 35982159 Zhou X et al. (2022)
c.1789C>G p.Leu597Val missense_variant Unknown - - 35741772 Hu C et al. (2022)
c.436C>T p.Arg146Trp missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.622A>G p.Ile208Val missense_variant De novo - - 33004838 Wang T et al. (2020)
c.722C>T p.Thr241Met missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.752G>A p.Cys251Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1357C>G p.Pro453Ala missense_variant De novo - - 33004838 Wang T et al. (2020)
c.1490C>T p.Ala497Val missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1552G>T p.Gly518Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1593G>C p.Trp531Cys missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1595G>A p.Cys532Tyr missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1673G>A p.Arg558Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1673G>T p.Arg558Leu missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1820C>T p.Ser607Phe missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.2012G>A p.Arg671Gln missense_variant Unknown - - 33004838 Wang T et al. (2020)
c.1410A>C p.Ser470%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.1713G>T p.Trp571Cys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.2296C>T p.Arg766Cys missense_variant Unknown - - 34615535 Mahjani B et al. (2021)
c.35C>T p.Ala12Val missense_variant De novo - Simplex 35982159 Zhou X et al. (2022)
c.722C>T p.Thr241Met missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1399T>G p.Ser467Ala missense_variant De novo - - 25363760 De Rubeis S , et al. (2014)
c.1495A>G p.Lys499Glu missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1501G>A p.Glu501Lys missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.2279A>G p.Tyr760Cys missense_variant Unknown - - 38438125 Tamam Khalaf et al. (2024)
c.1497A>C p.Lys499Asn missense_variant De novo - Simplex 35266334 Wang Q et al. (2022)
c.1455G>C p.Leu485Phe missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.1801A>C p.Lys601Gln missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.1914T>A p.Ala638%3D missense_variant Unknown - Unknown 33753861 Chen JS et al. (2021)
c.722C>T p.Thr241Met missense_variant De novo - Simplex 30414707 Okuzono S et al. (2019)
c.770A>G p.Gln257Arg missense_variant De novo - Simplex 31130284 Monies D , et al. (2019)
c.722C>T p.Thr241Met missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1593G>T p.Trp531Cys missense_variant De novo - Simplex 33644862 Hiraide T et al. (2021)
c.1574T>C p.Leu525Pro missense_variant De novo - Simplex 38764027 Ruohao Wu et al. (2024)
c.1406G>A p.Gly469Glu missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.1574T>C p.Leu525Pro missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.1593G>C p.Trp531Cys missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.1783T>C p.Phe595Leu missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.1801A>C p.Lys601Gln missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.2126A>G p.Gln709Arg missense_variant Unknown - Unknown 24458522 Alfieri P , et al. (2014)
c.418G>A p.Cys140Tyr missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
c.625A>T p.Lys209Ile missense_variant De novo - Simplex 25533962 Deciphering Developmental Disorders Study (2014)
Common Variants  

No common variants reported.

SFARI Gene score
1S

High Confidence, Syndromic

Score Delta: Score remained at 1S

criteria met
See SFARI Gene'scoring criteria
1

High Confidence

See all Category 1 Genes

We considered a rigorous statistical comparison between cases and controls, yielding genome-wide statistical significance, with independent replication, to be the strongest possible evidence for a gene. These criteria were relaxed slightly for category 2.

S

Syndromic

See all Category S Genes

The syndromic category includes mutations that are associated with a substantial degree of increased risk and consistently linked to additional characteristics not required for an ASD diagnosis. If there is independent evidence implicating a gene in idiopathic ASD, it will be listed as "#S" (e.g., 2S, 3S, etc.). If there is no such independent evidence, the gene will be listed simply as "S."

4/1/2021
1
icon
1

Score remained at 1

Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[Comorbidities associated with genetic abnormalities in children with intellectual disability2021]
1/1/2021
1
icon
1

Score remained at 1

Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[Genetic and phenotypic analysis of 101 patients with developmental delay or intellectual disability using whole-exome sequencing2021]
10/1/2020
1
icon
1

Score remained at 1

Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[Prevalence and architecture of de novo mutations in developmental disorders2017] [Large-scale targeted sequencing identifies risk genes for neurodevelopmental disorders2020]
10/1/2019
S
icon
1

Increased from S to 1

New Scoring Scheme
Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[New Scoring Scheme]
7/1/2019
S
icon
S

Increased from S to S

Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[Lessons Learned from Large-Scale, First-Tier Clinical Exome Sequencing in a Highly Consanguineous Population.2019]
1/1/2016
S
icon
S

Increased from S to S

Description

Mutations in the BRAF gene are responsible for cardiofaciocutaneous syndrome (Nava et al., 2007). In two recent reports, patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Reports Added
[Cardio-facio-cutaneous and Noonan syndromes due to mutations in the RAS/MAPK signalling pathway: genotype-phenotype relationships and overlap with ...2007] [Autism traits in the RASopathies.2013] [Behavioral profile in RASopathies.2014] [Large-scale discovery of novel genetic causes of developmental disorders.2014] [Germline mutations in genes within the MAPK pathway cause cardio-facio-cutaneous syndrome.2006] [Germline KRAS and BRAF mutations in cardio-facio-cutaneous syndrome.2006] [Synaptic, transcriptional and chromatin genes disrupted in autism.2014]
Krishnan Probability Score

Score 0.44733567224881

Ranking 12672/25841 scored genes


[Show Scoring Methodology]
Krishnan and colleagues generated probability scores genome-wide by using a machine learning approach on a human brain-specific gene network. The method was first presented in Nat Neurosci 19, 1454-1462 (2016), and scores for more than 25,000 RefSeq genes can be accessed in column G of supplementary table 3 (see: http://www.nature.com/neuro/journal/v19/n11/extref/nn.4353-S5.xlsx). A searchable browser, with the ability to view networks of associated ASD risk genes, can be found at asd.princeton.edu.
Original Source
ExAC Score

Score 0.999978196042

Ranking 515/18225 scored genes


[Show Scoring Methodology]
The Exome Aggregation Consortium (ExAC) is a summary database of 60,706 exomes that has been widely used to estimate 'constraint' on mutation for individual genes. It was introduced by Lek et al. Nature 536, 285-291 (2016), and the ExAC browser can be found at exac.broadinstitute.org. The pLI score was developed as measure of intolerance to loss-of- function mutation. A pLI > 0.9 is generally viewed as highly constrained, and thus any loss-of- function mutations in autism in such a gene would be more likely to confer risk. For a full list of pLI scores see: ftp://ftp.broadinstitute.org/pub/ExAC_release/release0.3.1/functional_gene_constraint/fordist_cle aned_exac_nonTCGA_z_pli_rec_null_data.txt
Original Source
Sanders TADA Score

Score 0.93719177765285

Ranking 13443/18665 scored genes


[Show Scoring Methodology]
The TADA score ('Transmission and De novo Association') was introduced by He et al. PLoS Genet 9(8):e1003671 (2013), and is a statistic that integrates evidence from both de novo and transmitted mutations. It forms the basis for the claim of 65 individual genes being strongly associated with autism risk at a false discovery rate of 0.1 (Sanders et al. Neuron 87, 1215-1233 (2015)). The calculated TADA score for 18,665 RefSeq genes can be found in column P of Supplementary Table 6 in the Sanders et al. paper (the column headed 'tadaFdrAscSscExomeSscAgpSmallDel'), which represents a combined analysis of exome data and small de novo deletions (see www.cell.com/cms/attachment/2038545319/2052606711/mmc7.xlsx).
Original Source
Zhang D Score

Score 0.26871313042008

Ranking 3205/20870 scored genes


[Show Scoring Methodology]
The DAMAGES score (disease-associated mutation analysis using gene expression signatures), or D score, was developed to combine evidence from de novo loss-of- function mutation with evidence from cell-type- specific gene expression in the mouse brain (specifically translational profiles of 24 specific mouse CNS cell types isolated from 6 different brain regions). Genes with positive D scores are more likely to be associated with autism risk, with higher-confidence genes having higher D scores. This statistic was first presented by Zhang & Shen (Hum Mutat 38, 204- 215 (2017), and D scores for more than 20,000 RefSeq genes can be found in column M in supplementary table 2 from that paper.
Original Source
Interactome
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
ARMCX3 armadillo repeat containing, X-linked 3 Human Protein Binding 51566 Q9UH62
FKBPL FK506 binding protein like Human Protein Binding 63943 Q9UIM3
HRAS v-Ha-ras Harvey rat sarcoma viral oncogene homolog Human Protein Binding 3265 P01112
KCNC4 potassium voltage-gated channel, Shaw-related subfamily, member 4 Human Protein Binding 3749 Q03721
KIAA0141 KIAA0141 Human Protein Binding NM_014773 Q14154
LIPF Gastric triacylglycerol lipase Human Protein Binding 8513 P07098
MAP2K1 mitogen-activated protein kinase kinase 1 Human Protein Binding 5604 A4QPA9
RAB3GAP1 RAB3 GTPase activating protein subunit 1 (catalytic) Human Protein Binding 22930 C9J837
RAF1 v-raf-1 murine leukemia viral oncogene homolog 1 Human Protein Binding 5894 P04049
RPTOR regulatory associated protein of MTOR, complex 1 Human Protein Binding 57521 Q8N122
YWHAB tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, beta polypeptide Human Protein Binding 7529 P31946
YWHAH tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide Human Protein Binding 7533 Q04917
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