rs1064795331

Variant names:

• chr6-33440769-C-T
• rs1064795331
• NM_006772.3:c.1717C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_006772.3(SYNGAP1):​c.1717C>T​(p.Arg573Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:7 U:1
• Conservation: PhyloP100: -0.932

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.92
• PP5: Variant 6-33440769-C-T is Pathogenic according to our data. Variant chr6-33440769-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 421734.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=2, Likely_pathogenic=3}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.1717C>T	p.Arg573Trp	missense_variant	Exon 11 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.1717C>T	p.Arg573Trp	missense_variant	Exon 11 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.1717C>T	p.Arg573Trp	missense_variant	Exon 11 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.1717C>T	p.Arg573Trp	missense_variant	Exon 11 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.1717C>T	p.Arg573Trp	missense_variant	Exon 11 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1540C>T	p.Arg514Trp	missense_variant	Exon 9 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 31

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:7 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:3 Uncertain:1

Apr 05, 2020

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 03, 2022

3billion, Medical Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The variant has been previously reported as de novo in a similarly affected individual (PS2_S). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000421734, PMID:30581057, PS1_S).A different missense change at the same codon (p.Arg573Leu, p.Arg573Gln) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000521291,VCV001176819, PM5_M). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.758, 3CNET: 0.862, PP3_P). It is not observed in the gnomAD v2.1.1 dataset (PM2_M). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -

Jan 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 573 of the SYNGAP1 protein (p.Arg573Trp). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with SYNGAP1-related conditions (PMID: 30581057). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 421734). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on SYNGAP1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Apr 13, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:3

Nov 26, 2021

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); 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: 30581057) -

-

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Intellectual disability Pathogenic:1

Sep 10, 2020

Diagnostic Laboratory, Strasbourg University Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.;.;.;.
Eigen	Benign	0.054
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.43	N
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	3.5	M;M;.;.;M;M;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-6.7	.;.;.;D;.;D;D;.
REVEL	Pathogenic	0.76
Sift	Pathogenic	0.0	.;.;.;D;.;D;D;.
Sift4G	Pathogenic	0.0010	.;D;.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;D;D;.;.
Vest4		0.78, 0.79, 0.79, 0.77
MutPred		0.74		Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);Loss of disorder (P = 0.0852);.;.;
MVP		0.89
MPC		2.3
ClinPred		0.99	D
GERP RS		1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.57
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1064795331; hg19: chr6-33408546; COSMIC: COSV53384814; COSMIC: COSV53384814;