rs397514741

Variant names:

• chr6-33432724-C-T
• rs397514741
• NM_006772.3:c.427C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_006772.3(SYNGAP1):​c.427C>T​(p.Arg143*) variant causes a stop gained 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 Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10
• Conservation: PhyloP100: 0.690
• Publications: 11 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 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 6-33432724-C-T is Pathogenic according to our data. Variant chr6-33432724-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 60716.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.427C>T	p.Arg143*	stop_gained	Exon 5 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.427C>T	p.Arg143*	stop_gained	Exon 5 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.427C>T	p.Arg143*	stop_gained	Exon 5 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.427C>T	p.Arg143*	stop_gained	Exon 5 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.427C>T	p.Arg143*	stop_gained	Exon 5 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.250C>T	p.Arg84*	stop_gained	Exon 3 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 40

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:7

Dec 10, 2021

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PM2_SUP -

Jan 05, 2015

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (p.Arg143*) 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 premature translational stop signal has been observed in individual(s) with SYNGAP1-related conditions (PMID: 23708187, 30541864). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 60716). For these reasons, this variant has been classified as Pathogenic. -

-

Génétique des Maladies du Développement, Hospices Civils de Lyon

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 27, 2023

Department of Clinical Genetics, Medical University of Lodz

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: literature only

- -

not provided Pathogenic:2

Jun 23, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23708187, 30541864, 31395010, 33144682, 31440721) -

Feb 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SYNGAP1: PS2:Very Strong, PVS1, PM2, PS4:Moderate -

Complex neurodevelopmental disorder Pathogenic:1

Apr 16, 2018

GenomeConnect - Simons Searchlight

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: provider interpretation

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-16 and interpreted as Pathogenic. Variant was initially reported on 2017-10-09 by GTR ID of laboratory name 500031. The reporting laboratory might also submit to ClinVar. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.48
CADD	Pathogenic	37
DANN	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
PhyloP100		0.69
Vest4		0.86, 0.87, 0.81, 0.83
GERP RS		3.5
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs397514741; hg19: chr6-33400501; COSMIC: COSV99537990; COSMIC: COSV99537990;