rs1554304258

Variant names:

• chr6-33420306-CG-C
• rs1554304258
• NM_006772.3:c.43delG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006772.3(SYNGAP1):​c.43delG​(p.Ala15ArgfsTer54) 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. A15A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 28)
• Consequence: SYNGAP1 NM_006772.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.48
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 5

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae)
• autosomal dominant non-syndromic intellectual disability

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• SYNGAP1-related developmental and epileptic encephalopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myoclonic-astatic epilepsy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 365 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 6-33420306-CG-C is Pathogenic according to our data. Variant chr6-33420306-CG-C is described in ClinVar as Pathogenic. ClinVar VariationId is 521836.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.43delG	p.Ala15ArgfsTer54	frameshift_variant	Exon 1 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.43delG	p.Ala15ArgfsTer54	frameshift_variant	Exon 1 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.43delG	p.Ala15ArgfsTer54	frameshift_variant	Exon 1 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.43delG	p.Ala15ArgfsTer54	frameshift_variant	Exon 1 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.43delG	p.Ala15ArgfsTer54	frameshift_variant	Exon 1 of 19	5		ENSP00000403636.3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

May 31, 2017

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.43delG pathogenic mutation, located in coding exon 1 of the SYNGAP1 gene, results from a deletion of one nucleotide at nucleotide position 43, causing a translational frameshift with a predicted alternate stop codon (p.A15Rfs*54). This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.5
Mutation Taster		=6/194	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1554304258; hg19: chr6-33388083;