chr6-33420312-G-A

Position:

• chr6-33420312-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006772.3(SYNGAP1):​c.48G>A​(p.Met16Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,714 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.68

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.12835497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.48G>A	p.Met16Ile	missense_variant	1/19	ENST00000646630.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.48G>A	p.Met16Ile	missense_variant	1/19		NM_006772.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151714 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1389488 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 685128

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151714 Hom.: 0 Cov.: 28 AF XY: 0.0000135 AC XY: 1 AN XY: 74090

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2021

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt SYNGAP1 protein function. This variant has not been reported in the literature in individuals affected with SYNGAP1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This sequence change replaces methionine with isoleucine at codon 16 of the SYNGAP1 protein (p.Met16Ile). The methionine residue is weakly conserved and there is a small physicochemical difference between methionine and isoleucine. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.051	T;T;.;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.79	.;T;T;T;T;T
M_CAP	Benign	0.078	D
MetaRNN	Benign	0.13	T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N;.;.;N;N
MutationTaster	Benign	0.67	N;N;N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.15	.;.;.;N;.;N
REVEL	Benign	0.057
Sift	Pathogenic	0.0	.;.;.;D;.;D
Sift4G	Benign	0.20	.;T;.;T;T;T
Polyphen		0.0	B;B;.;B;B;.
Vest4		0.29, 0.36, 0.30
MutPred		0.31		Loss of MoRF binding (P = 0.0788);Loss of MoRF binding (P = 0.0788);Loss of MoRF binding (P = 0.0788);Loss of MoRF binding (P = 0.0788);Loss of MoRF binding (P = 0.0788);Loss of MoRF binding (P = 0.0788);
MVP		0.15
MPC		1.2
ClinPred		0.34	T
GERP RS		3.7
Varity_R		0.36
gMVP		0.51

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: rs1776745451; hg19: chr6-33388089;