chr6-33420291-TC-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate

The NM_006772.3(SYNGAP1):​c.28del​(p.Arg10GlyfsTer59) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R10R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 28)

Consequence

SYNGAP1
NM_006772.3 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 1.91
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 237 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 6-33420291-TC-T is Pathogenic according to our data. Variant chr6-33420291-TC-T is described in ClinVar as [Pathogenic]. Clinvar id is 2808095.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SYNGAP1NM_006772.3 linkuse as main transcriptc.28del p.Arg10GlyfsTer59 frameshift_variant 1/19 ENST00000646630.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SYNGAP1ENST00000646630.1 linkuse as main transcriptc.28del p.Arg10GlyfsTer59 frameshift_variant 1/19 NM_006772.3 P1Q96PV0-1

Frequencies

GnomAD3 genomes
Cov.:
28
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
28
Bravo
AF:
0.00000378

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 24, 2023This sequence change creates a premature translational stop signal (p.Arg10Glyfs*59) in the SYNGAP1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23161826, 23708187, 26989088). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1776744347; hg19: chr6-33388068; API