chr6-33444450-C-CA

Variant names:

• chr6-33444450-C-CA
• rs1554122458
• NM_006772.3:c.3416dupA

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006772.3(SYNGAP1):​c.3416dupA​(p.Thr1140AspfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SYNGAP1 NM_006772.3 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 6.29

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 Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33444450-C-CA is Pathogenic according to our data. Variant chr6-33444450-C-CA is described in ClinVar as [Pathogenic]. Clinvar id is 522008.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	c.3416dupA	p.Thr1140AspfsTer13	frameshift_variant	Exon 16 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3416dupA	p.Thr1140AspfsTer13	frameshift_variant	Exon 16 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.3416dupA	p.Thr1140AspfsTer13	frameshift_variant	Exon 16 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.3374dupA	p.Thr1126AspfsTer13	frameshift_variant	Exon 15 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.3416dupA	p.Thr1140AspfsTer13	frameshift_variant	Exon 16 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.3239dupA	p.Thr1081AspfsTer13	frameshift_variant	Exon 14 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:2

Jul 09, 2021

New York Genome Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The de novo c.3416dup (p.Thr1140AspfsTer13) variant identified in the SYNGAP1 gene is the duplication of a single nucleotide resulting in a frameshift at amino acid 1139/1344 (exon 16/19) and is predicted to lead to the premature termination of the protein approximately 13 amino acids downstream. This variant is absent from gnomAD(v3.1.1) suggesting it is not a common benign variant in the populations represented in that database. The c.3416dup (p.Thr1140AspfsTer13 )variant is reported in ClinVar as Pathogenic (VarID:522008) and has been reported as a de novo variant in one affected individual in the literature (published as c.3415insA; p.Thr1140AspfsTer13) with refractory epilepsy, developmental delay, and autism [PMID:32730690]. Given its presence de novo here, absence in population databases, and observation de novo in an affected individual in the literature, the c.3416dup (p.Thr1140AspfsTer13) variant identified in the SYNGAP1 gene of this individual is reported as Pathogenic. -

Oct 18, 2018

Undiagnosed Diseases Network, NIH

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Sep 25, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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

LitVar

Other links and lift over

dbSNP: rs1554122458; hg19: chr6-33412227;