rs1060503384

Variant names:

• chr6-33441612-G-A
• rs1060503384
• NM_006772.3:c.2147G>A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2 PP2 PP5 BP4

The NM_006772.3(SYNGAP1):​c.2147G>A​(p.Arg716Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1
• Conservation: PhyloP100: 6.53

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

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.
• PP5: Variant 6-33441612-G-A is Pathogenic according to our data. Variant chr6-33441612-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 411585.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.37220588). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3	c.2147G>A	p.Arg716Gln	missense_variant	Exon 13 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.2147G>A	p.Arg716Gln	missense_variant	Exon 13 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1	c.2147G>A	p.Arg716Gln	missense_variant	Exon 13 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7	c.2147G>A	p.Arg716Gln	missense_variant	Exon 13 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7	c.2147G>A	p.Arg716Gln	missense_variant	Exon 13 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1	c.1970G>A	p.Arg657Gln	missense_variant	Exon 11 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 250946 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135796

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Intellectual disability, autosomal dominant 5 Pathogenic:1

Jul 19, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been observed in individual(s) with clinical features of developmental and epileptic encephalopathy (Invitae). In at least one individual the variant was observed to be de novo. For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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 expected to disrupt SYNGAP1 protein function. ClinVar contains an entry for this variant (Variation ID: 411585). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 716 of the SYNGAP1 protein (p.Arg716Gln). -

not provided Uncertain:1

Jan 22, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Reported in one individual from a large cohort of patients with epilepsy, however further clinical information was not provided (PMID: 31440721); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31395010, 31440721) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.050	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.56	D;D;.;.;.;.;.;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.96	.;D;D;D;D;D;D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.37	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.5	M;M;.;.;M;M;.;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.0	.;.;.;D;.;D;D;.
REVEL	Benign	0.21
Sift	Benign	0.039	.;.;.;D;.;D;D;.
Sift4G	Uncertain	0.0070	.;D;.;D;D;D;D;.
Polyphen		1.0	D;D;.;.;D;D;.;.
Vest4		0.40, 0.40, 0.44, 0.40
MutPred		0.36		Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);Loss of MoRF binding (P = 0.0523);.;.;
MVP		0.39
MPC		2.5
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.43
gMVP		0.78

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs1060503384; hg19: chr6-33409389; COSMIC: COSV99538844; COSMIC: COSV99538844;