6-33437760-C-CCTGGATGA

Variant names:

• chr6-33437760-C-CCTGGATGA
• rs1554121189
• NM_006772.3:c.857_864dupTGGATGAC

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.857_864dupTGGATGAC​(p.Met289TrpfsTer61) 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 (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.83
• 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-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 12 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 6-33437760-C-CCTGGATGA is Pathogenic according to our data. Variant chr6-33437760-C-CCTGGATGA is described in ClinVar as Pathogenic. ClinVar VariationId is 469164.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006772.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	NM_006772.3	MANE Select	c.857_864dupTGGATGAC	p.Met289TrpfsTer61	frameshift	Exon 8 of 19	NP_006763.2
	SYNGAP1	NM_001130066.2		c.857_864dupTGGATGAC	p.Met289TrpfsTer61	frameshift	Exon 8 of 18	NP_001123538.1
	SYNGAP1-AS1	NR_174954.1		n.330-287_330-280dupTCATCCAG		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SYNGAP1	ENST00000646630.1	MANE Select	c.857_864dupTGGATGAC	p.Met289TrpfsTer61	frameshift	Exon 8 of 19	ENSP00000496007.1
	SYNGAP1	ENST00000644458.1		c.857_864dupTGGATGAC	p.Met289TrpfsTer61	frameshift	Exon 8 of 19	ENSP00000495541.1
	SYNGAP1	ENST00000449372.7	TSL:5	c.857_864dupTGGATGAC	p.Met289TrpfsTer61	frameshift	Exon 8 of 18	ENSP00000416519.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1

Apr 08, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. While this particular variant has not been reported in the literature, loss-of-function variants in SYNGAP1 are known to be pathogenic (PMID: 23708187, 23161826). ClinVar contains an entry for this variant (Variation ID: 469164). This sequence change inserts 8 nucleotide in exon 8 of the SYNGAP1 mRNA (c.857_864dupTGGATGAC), causing a frameshift at codon 289. This creates a premature translational stop signal (p.Met289Trpfs*61) and is expected to result in an absent or disrupted protein product.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=1/199	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1554121189; hg19: chr6-33405537;