rs397514670

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_006772.3(SYNGAP1):c.1685C>T(p.Pro562Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1

Conservation

PhyloP100: 7.90

Publications

7 publications found

Variant links:

Genes affected

SYNGAP1 (HGNC:11497): (synaptic Ras GTPase activating protein 1) This gene encodes a Ras GTPase activating protein that is a member of the N-methyl-D-aspartate receptor complex. The N-terminal domain of the protein contains a Ras-GAP domain, a pleckstrin homology domain, and a C2 domain that may be involved in binding of calcium and phospholipids. The C-terminal domain consists of a ten histidine repeat region, serine and tyrosine phosphorylation sites, and a T/SXV motif required for postsynaptic scaffold protein interaction. The encoded protein negatively regulates Ras, Rap and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor trafficking to the postsynaptic membrane to regulate synaptic plasticity and neuronal homeostasis. Allelic variants of this gene are associated with intellectual disability and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

SYNGAP1 links:

SYNGAP1-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

SYNGAP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

PP5

Variant 6-33440737-C-T is Pathogenic according to our data. Variant chr6-33440737-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 41462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.1685C>T	p.Pro562Leu	missense_variant	Exon 11 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYNGAP1	ENST00000646630.1 link	c.1685C>T	p.Pro562Leu	missense_variant	Exon 11 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1 link	c.1685C>T	p.Pro562Leu	missense_variant	Exon 11 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7 link	c.1685C>T	p.Pro562Leu	missense_variant	Exon 11 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7 link	c.1685C>T	p.Pro562Leu	missense_variant	Exon 11 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1 link	c.1508C>T	p.Pro503Leu	missense_variant	Exon 9 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1434586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

711490

African (AFR)

AF:

0.00

AC:

AN:

32666

American (AMR)

AF:

0.00

AC:

AN:

39850

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25628

East Asian (EAS)

AF:

0.00

AC:

AN:

38014

South Asian (SAS)

AF:

0.00

AC:

AN:

83154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51794

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1098322

Other (OTH)

AF:

0.00

AC:

AN:

59420

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 5

Pathogenic:4Uncertain:1

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2019

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance:Uncertain significance

Review Status:flagged submission

Collection Method:clinical testing

- -

Aug 09, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ClinVar contains an entry for this variant (Variation ID: 41462). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects SYNGAP1 function (PMID: 23161826). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt SYNGAP1 protein function. This missense change has been observed in individual(s) with intellectual disability and epilepsy (PMID: 23161826, 26989088; Invitae). In at least one individual the variant was observed to be de novo. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 562 of the SYNGAP1 protein (p.Pro562Leu). -

not provided

Pathogenic:2

Jan 23, 2023

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: loss of protein function (Berryer et al., 2013; Zeng et al., 2017); Not observed in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30541864, 23161826, 28576131, 26989088, 28524815, 33308442, 33639450) -

Sep 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SYNGAP1: PS2, PM2, PS4:Moderate, PP2, PP3 -

Autosomal dominant epilepsy

Pathogenic:1

Mar 23, 2023

Rare Disease Center, Seoul National University Hospital

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Inborn genetic diseases

Pathogenic:1

Sep 21, 2017

Ambry Genetics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Complex neurodevelopmental disorder

Pathogenic:1

Jun 01, 2018

GenomeConnect - Simons Searchlight

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-06-01 and interpreted as Pathogenic. Variant was initially reported on 2017-02-13 by GTR ID of laboratory name 26957. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.91

D;D;.;.;.;.;.;.

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.90

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

1.0

.;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.36

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.29

MutationAssessor

Pathogenic

3.6

H;H;.;.;H;H;.;.

PhyloP100

7.9

PrimateAI

Pathogenic

0.91

PROVEAN

Pathogenic

-9.7

.;.;.;D;.;D;D;.

REVEL

Pathogenic

0.83

Sift

Uncertain

0.0010

.;.;.;D;.;D;D;.

Sift4G

Pathogenic

0.0

.;D;.;D;D;D;D;.

Polyphen

1.0

D;D;.;.;D;D;.;.

Vest4

0.96, 0.94, 0.94, 0.95

MutPred

0.94

Loss of methylation at K566 (P = 0.0736);Loss of methylation at K566 (P = 0.0736);Loss of methylation at K566 (P = 0.0736);Loss of methylation at K566 (P = 0.0736);Loss of methylation at K566 (P = 0.0736);Loss of methylation at K566 (P = 0.0736);.;.;

MVP

0.97

MPC

2.3

ClinPred

1.0

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.88

gMVP

0.99

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over