chr6-33437786-C-T

Position:

• chr6-33437786-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_006772.3(SYNGAP1):​c.881C>T​(p.Thr294Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SYNGAP1. . Gene score misZ 5.6047 (greater than the threshold 3.09). Trascript score misZ 7.6762 (greater than threshold 3.09). GenCC has associacion of gene with autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.868

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.881C>T	p.Thr294Ile	missense_variant	8/19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.881C>T	p.Thr294Ile	missense_variant	8/19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.881C>T	p.Thr294Ile	missense_variant	8/19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.881C>T	p.Thr294Ile	missense_variant	8/18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.881C>T	p.Thr294Ile	missense_variant	8/19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.704C>T	p.Thr235Ile	missense_variant	6/17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2021

This sequence change replaces threonine with isoleucine at codon 294 of the SYNGAP1 protein (p.Thr294Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This missense change has been observed in individual(s) with global developmental delay and epilepsy (Invitae). In at least one individual the variant was observed to be de novo. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.91
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Pathogenic	0.99	.;D;D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.3	M;M;.;.;M;M;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.5	.;.;.;D;.;D;D;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	.;.;.;D;.;D;D;.
Sift4G	Pathogenic	0.0	.;D;.;D;D;D;D;.
Polyphen		1.0	D;D;.;D;D;D;.;.
Vest4		0.48, 0.93, 0.57, 0.90
MutPred		0.47		Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);Loss of disorder (P = 0.0344);.;.;
MVP		0.83
MPC		2.4
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.18
gMVP		0.97

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: rs1554121191; hg19: chr6-33405563;