Human Gene Module / Chromosome 11 / HRAS

HRASv-Ha-ras Harvey rat sarcoma viral oncogene homolog

Score
4
Minimal Evidence Criteria 4.1
Autism Reports / Total Reports
4 / 11
Rare Variants / Common Variants
7 / 8
Aliases
HRAS, HRAS1,  K-ras,  N-ras,  RASH1,  c-bas/has
Associated Syndromes
Costello syndrome
Genetic Category
Rare Single Gene Mutation, Syndromic, Genetic Association
Chromosome Band
11p15.5
Associated Disorders
ASD, DD/NDD
Relevance to Autism

Studies have found genetic association between the HRAS gene and autism in French-Caucasian and US-Caucasian population cohorts. In addition, variants in HRAS have been identified with Costello syndrome (Sol-Church et al., 2006).

Molecular Function

The encoded protein binds GTP and has GTPase activity.

Reports related to HRAS (11 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Highly Cited The latent nuclear antigen of Kaposi sarcoma-associated herpesvirus targets the retinoblastoma-E2F pathway and with the oncogene Hras transforms pr... Radkov SA , et al. (2000) No -
2 Recent Recommendation Oncogenic HRAS suppresses clusterin expression through promoter hypermethylation. Lund P , et al. (2006) No -
3 Recent Recommendation Paternal bias in parental origin of HRAS mutations in Costello syndrome. Sol-Church K , et al. (2006) No -
4 Support High-throughput sequencing of mGluR signaling pathway genes reveals enrichment of rare variants in autism. Kelleher RJ 3rd , et al. (2012) Yes -
5 Recent Recommendation Autism traits in the RASopathies. Adviento B , et al. (2013) No Autistic features
6 Recent Recommendation Behavioral profile in RASopathies. Alfieri P , et al. (2014) No Autistic features
7 Support Behavioral phenotype in Costello syndrome with atypical mutation: a case report. Alfieri P , et al. (2014) No ASD (PDD-NOS)
8 Support Aberrant HRAS transcript processing underlies a distinctive phenotype within the RASopathy clinical spectrum. Pantaleoni F , et al. (2017) No -
9 Positive Association Autism and genetics: clinical approach and association study with two markers of HRAS gene. Hrault J , et al. (1995) Yes -
10 Primary Possible association of c-Harvey-Ras-1 (HRAS-1) marker with autism. Hrault J , et al. (1993) Yes -
11 Positive Association Studies of the c-Harvey-Ras gene in psychiatric disorders. Comings DE , et al. (1996) Yes -
Rare Variants   (7)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.34G>A p.Gly12Ser missense_variant - - - 16835863 Sol-Church K , et al. (2006)
c.35G>C p.Gly12Ala missense_variant De novo - - 16835863 Sol-Church K , et al. (2006)
c.37G>A p.Gly13Cys missense_variant De novo - - 16835863 Sol-Church K , et al. (2006)
c.498C>G p.(=) synonymous_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.383G>A p.Arg128Gln missense_variant - - Multiplex 22558107 Kelleher RJ 3rd , et al. (2012)
c.108_110dupAGA p.Glu37dup inframe_insertion Unknown - Unknown 25367099 Alfieri P , et al. (2014)
c.481_490delGGGACCCTCT p.Leu163ProfsTer52 frameshift_variant De novo - - 28390077 Pantaleoni F , et al. (2017)
Common Variants   (8)
Status Allele Change Residue Change Variant Type Inheritance Pattern Paternal Transmission Family Type PubMed ID Author, Year
N/A N/A allele - - - 8098541 Hrault J , et al. (1993)
N/A N/A gene_variant - - - 7485261 Hrault J , et al. (1995)
N/A N/A microsatellite - - - 7485261 Hrault J , et al. (1995)
N/A N/A microsatellite - - - 8832771 Comings DE , et al. (1996)
c.111+15G>A - intron_variant - - - 16835863 Sol-Church K , et al. (2006)
c.-10C>T - 2KB_upstream_variant - - - 16835863 Sol-Church K , et al. (2006)
c.81T>C p.(=) synonymous_variant - - - 16835863 Sol-Church K , et al. (2006)
N/A N/A microsatellite, intron_variant - - - 16835863 Sol-Church K , et al. (2006)
SFARI Gene score
4

Minimal Evidence

4

Score Delta: Score remained at 4.3

4

Minimal Evidence

See all Category 4 Genes

The literature is replete with relatively small studies of candidate genes, using either common or rare variant approaches, which do not reach the criteria set out for categories 1 and 2. Genes that had two such lines of supporting evidence were placed in category 3, and those with one line of evidence were placed in category 4. Some additional lines of "accessory evidence" (indicated as 'acc" in the score cards) could also boost a gene from category 4 to 3.

10/1/2014
4
icon
4

Score remained at 4

Description

Two single marker studies from one group report association and replication of association, although neither is significant under current genome-wide criteria (case-control report by Comings et al. has only 48 subjects). Twelve out of thirteen individuals with Costello syndrome, characterized by mental retardation and carcinomas, show mutations in HRAS.

7/1/2014
No data
icon
4

Increased from No data to 4

Description

Two single marker studies from one group report association and replication of association, although neither is significant under current genome-wide criteria (case-control report by Comings et al. has only 48 subjects). Twelve out of thirteen individuals with Costello syndrome, characterized by mental retardation and carcinomas, show mutations in HRAS.

4/1/2014
No data
icon
4

Increased from No data to 4

Description

Two single marker studies from one group report association and replication of association, although neither is significant under current genome-wide criteria (case-control report by Comings et al. has only 48 subjects). Twelve out of thirteen individuals with Costello syndrome, characterized by mental retardation and carcinomas, show mutations in HRAS.

Krishnan Probability Score

Score 0.44730206597492

Ranking 12845/25841 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.
ExAC Score

Score 0.007941049302842

Ranking 10193/18225 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
Sanders TADA Score

Score 0.91073757850585

Ranking 7628/18665 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).
Larsen Cumulative Evidence Score

Score 10

Ranking 187/461 scored genes


[Show Scoring Methodology]
Larsen and colleagues generated gene scores based on the sum of evidence for all available ASD-associated variants in a gene, with assessments based on mode of inheritance, effect size, and variant frequency in the general population. The approach was first presented in Mol Autism 7:44 (2016), and scores for 461 genes can be found in column I in supplementary table 4 from that paper.
Zhang D Score

Score -0.12211564091477

Ranking 13210/20870 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.
CNVs associated with HRAS(1 CNVs)
11p15.5 20 Deletion-Duplication 32  /  68
Interaction Table
Interactor Symbol Interactor Name Interactor Organism Interactor Type Entrez ID Uniprot ID
C1ORF93 Prostamide/prostaglandin F synthase Human Protein Binding 127281 Q8TBF2-5
C1QL4 complement component 1, q subcomponent-like 4 Human Protein Binding 338761 Q86Z23
CD27 CD27 antigen Human Protein Binding 939 P26842
DEFB104A Beta-defensin 104 Human Protein Binding 140596 Q8WTQ1
RIN1 Ras and Rab interactor 1 Human Protein Binding 9610 Q13671
S1PR1 Sphingosine 1-phosphate receptor 1 Human Protein Binding 1901 P21453
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