rs1057518352

Positions:

• chr6-33432787-C-T

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.490C>T​(p.Arg164*) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 1.78

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 (HGNC:):

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 6-33432787-C-T is Pathogenic according to our data. Variant chr6-33432787-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373327.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.490C>T	p.Arg164*	stop_gained	5/19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.490C>T	p.Arg164*	stop_gained	5/19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.490C>T	p.Arg164*	stop_gained	5/19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.490C>T	p.Arg164*	stop_gained	5/18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.490C>T	p.Arg164*	stop_gained	5/19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.313C>T	p.Arg105*	stop_gained	3/17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:6

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 17, 2022	This sequence change creates a premature translational stop signal (p.Arg164*) 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). For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 373327). This premature translational stop signal has been observed in individual(s) with SYNGAP1-related conditions (PMID: 26989088, 28708303, 30541864). This variant is not present in population databases (gnomAD no frequency). -
Pathogenic, criteria provided, single submitter	clinical testing	Groupe Hospitalier Pitie Salpetriere, UF Genomique du Developpement, Assistance Publique Hopitaux de Paris	Jan 06, 2017	Intellectual disability, severe; epilepsy; autism -
Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1+PM2_Supporting+PS4_Moderate+PM6 -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Jun 03, 2020	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 08, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Apr 18, 2023	This variant was identified as de novo (maternity and paternity confirmed)._x000D_ Criteria applied: PVS1, PS2, PS4_MOD, PM2_SUP -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 06, 2023	Identified in two siblings with developmental delay and seizures previously tested at GeneDx who inherited the variant from an unaffected parent who is mosaic; 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: 34800434, 30541864, 26989088, 28191889, 31031587, 28708303, 37583270) -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2018	- -

Complex neurodevelopmental disorder Pathogenic:1

Pathogenic, no assertion criteria provided

provider interpretation

GenomeConnect - Simons Searchlight

Apr 27, 2018

Submission from Simons Searchlight facilitated by GenomeConnect. Variant interpreted by the Simons Searchlight team most recently on 2018-04-27 and interpreted as Pathogenic. The reporting laboratory might also submit to ClinVar. This variant was identified in multiple probands enrolled in Simons Searchlight and, in one family, was identified in multiple siblings. Additional phenotypic information for other sibling(s) might be available from Simons Searchlight. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.80	D
Vest4		0.88, 0.90, 0.81
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1057518352; hg19: chr6-33400564; COSMIC: COSV53385610; COSMIC: COSV53385610;