Human Gene Module / Chromosome 6 / SYNCRIP

SYNCRIPsynaptotagmin binding cytoplasmic RNA interacting protein

SFARI Gene Score
2
Strong Candidate Criteria 2.1
Autism Reports / Total Reports
5 / 10
Rare Variants / Common Variants
33 / 0
Aliases
SYNCRIP, GRY-RBP,  GRYRBP,  HNRNPQ,  HNRPQ1,  NSAP1,  PP68,  hnRNP-Q
Associated Syndromes
-
Chromosome Band
6q14.3
Associated Disorders
ADHD, EPS
Relevance to Autism

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017); additional phenotypic characterization of these individuals in Gillentine et al., 2021 found that one of these individuals presented with autism spectrum disorder in addition to developmental delay and intellectual disability. Genetic and phenotypic characterization of 27 individuals with SYNCRIP variants in Gillentine et al., 2021 found that affected individuals frequently presented with developmental delay/intellectual disability/specific learning disability (23/27 patients) and autism spectrum disorder (15/26 patients).

Molecular Function

This gene encodes a member of the cellular heterogeneous nuclear ribonucleoprotein (hnRNP) family. hnRNPs are RNA binding proteins that complex with heterogeneous nuclear RNA (hnRNA) and regulate alternative splicing, polyadenylation, and other aspects of mRNA metabolism and transport. The encoded protein plays a role in multiple aspects of mRNA maturation and is associated with several multiprotein complexes including the apoB RNA editing-complex and survival of motor neurons (SMN) complex.

External Links
Gene CardOpen Targets PlatformgnomAD browserPubMed
Human
Entrez GeneOMIMUniProtHumanBaseVariCarta
SFARI Genomic Platforms
GPF browser SFARI genome browser
Reports related to SYNCRIP (10 Reports)
# Type Title Author, Year Autism Report Associated Disorders
1 Support Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study Rauch A , et al. (2012) No Epilepsy/seizures
2 Primary Excess of rare, inherited truncating mutations in autism Krumm N , et al. (2015) Yes -
3 Support Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability Lelieveld SH et al. (2016) No -
4 Support Prevalence and architecture of de novo mutations in developmental disorders et al. (2017) No -
5 Recent Recommendation Genome sequencing identifies multiple deleterious variants in autism patients with more severe phenotypes Guo H , et al. (2018) Yes -
6 Support Inherited and multiple de novo mutations in autism/developmental delay risk genes suggest a multifactorial model Guo H , et al. (2018) Yes -
7 Recent Recommendation - Gillentine MA et al. (2021) Yes ADHD, epilepsy/seizures
8 Support - Semino F et al. (2021) No ASD or autistic features, stereotypy, epilepsy/sei
9 Support - Zhou X et al. (2022) Yes -
10 Support - Erica Rosina et al. (2024) No -
Rare Variants   (33)
Status Allele Change Residue Change Variant Type Inheritance Pattern Parental Transmission Family Type PubMed ID Author, Year
c.114A>G p.Lys38%3D synonymous_variant De novo - - 35982159 Zhou X et al. (2022)
c.149-2A>G - splice_site_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.734T>C p.Leu245Pro missense_variant De novo - - 34157790 Semino F et al. (2021)
c.1281-1G>A - splice_site_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1299T>G p.Tyr433Ter stop_gained De novo - - 33874999 Gillentine MA et al. (2021)
c.1336C>T p.Arg446Ter stop_gained De novo - - 33874999 Gillentine MA et al. (2021)
c.1416T>G p.Tyr472Ter stop_gained De novo - - 33874999 Gillentine MA et al. (2021)
c.327dup p.Val110CysfsTer14 frameshift_variant De novo - - 28135719 et al. (2017)
c.629T>C p.Phe210Ser missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.429G>C p.Lys143Asn missense_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.498C>G p.Ser166Arg missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.611G>A p.Gly204Asp missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1595C>T p.Ala532Val missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.1648G>A p.Val550Ile missense_variant Unknown - - 33874999 Gillentine MA et al. (2021)
c.932dup p.Asp312ArgfsTer20 frameshift_variant De novo - - 23020937 Rauch A , et al. (2012)
c.1353+207del - frameshift_variant Unknown Not maternal Simplex 30564305 Guo H , et al. (2018)
c.201del p.Phe67LeufsTer29 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.560dup p.Asn187LysfsTer8 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.683dup p.Glu229ArgfsTer4 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.980dup p.Asn327LysfsTer5 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.560dup p.Asn187LysfsTer8 frameshift_variant De novo - Simplex 34157790 Semino F et al. (2021)
c.921del p.Phe307LeufsTer161 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1196_1213dup p.Gly399_Gly404dup inframe_indel De novo - Simplex 25961944 Krumm N , et al. (2015)
c.787_790del p.Phe263AlafsTer3 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1438G>A p.Gly480Arg missense_variant Unknown Not maternal - 33874999 Gillentine MA et al. (2021)
c.858_859del p.Gly287LeufsTer5 frameshift_variant De novo - Simplex 34157790 Semino F et al. (2021)
c.953_956del p.Arg318LysfsTer149 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1051_1052del p.Glu351ArgfsTer8 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1247_1250del p.Arg416LysfsTer148 frameshift_variant De novo - - 27479843 Lelieveld SH et al. (2016)
NM_001159676.1:c.1574A>T p.Gln525Leu missense_variant De novo - Simplex 30504930 Guo H , et al. (2018)
c.787_790del p.Phe263AlafsTer3 frameshift_variant De novo - Simplex 38041506 Erica Rosina et al. (2024)
c.319_320insGGTGT p.Tyr107TrpfsTer64 frameshift_variant De novo - - 33874999 Gillentine MA et al. (2021)
c.1196dup p.Arg400LysfsTer4 frameshift_variant Unknown Not paternal - 33874999 Gillentine MA et al. (2021)
Common Variants  

No common variants reported.

SFARI Gene score
2

Strong Candidate

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017).

Score Delta: Score remained at 2

criteria met
See SFARI Gene'scoring criteria
2

Strong Candidate

See all Category 2 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.

4/1/2022
3
icon
2

Decreased from 3 to 2

Description

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017).

4/1/2021
3
icon
3

Decreased from 3 to 3

Description

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017).

Reports Added
[Rare deleterious mutations of HNRNP genes result in shared neurodevelopmental disorders2021]
10/1/2019
4
icon
3

Decreased from 4 to 3

New Scoring Scheme
Description

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017).

Reports Added
[New Scoring Scheme]
10/1/2018
icon
4

Increased from to 4

Description

A de novo in-frame variant in the SYNCRIP gene was identified in an ASD proband from the Simons Simplex Collection in Krumm et al., 2015. Whole genome sequencing of a cohort of 180 simplex and multiplex ASD families in Guo et al., 2018 identified two rare de novo missense variants in the SYNCRIP gene in ASD probands; statistical analysis demonstrated that the probability of finding two de novo missense variants within this gene in this cohort was significantly low (P = 8.7E-07, adjusted P-value 0.02, one-tailed binomial test). De novo loss-of-function variants in the SYNCRIP gene have also been observed in individuals with developmental delay and/or intellectual disability (Rauch et al., 2012; Lelieveld et al., 2016; Deciphering Developmental Disorders Study 2017).

Krishnan Probability Score

Score 0.56793537825018

Ranking 1150/25841 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 0.99937859141528

Ranking 977/18225 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 0.24904948846735

Ranking 142/18665 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 0.15464876908244

Ranking 5088/20870 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
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