rs191549504

Positions:

• chr6-33443896-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006772.3(SYNGAP1):​c.3344T>C​(p.Ile1115Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0136 in 1,512,836 control chromosomes in the GnomAD database, including 183 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0091 (11 hom., cov: 31)
  • Exomes 𝑓: 0.014 (172 hom.)
• Consequence: SYNGAP1 NM_006772.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.654

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 Benign. Variant got -19 ACMG points.

• 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=0.005625069).
• BP6: Variant 6-33443896-T-C is Benign according to our data. Variant chr6-33443896-T-C is described in ClinVar as [Benign]. Clinvar id is 130530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33443896-T-C is described in Lovd as [Benign]. Variant chr6-33443896-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00909 (1366/150224) while in subpopulation NFE AF= 0.0131 (882/67402). AF 95% confidence interval is 0.0124. There are 11 homozygotes in gnomad4. There are 697 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1366 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3	c.3344T>C	p.Ile1115Thr	missense_variant	15/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1	n.329+2710A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1	c.3344T>C	p.Ile1115Thr	missense_variant	15/19		NM_006772.3	P1
SYNGAP1-AS1	ENST00000630418.1	n.377+2710A>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00910 AC: 1366 AN: 150108 Hom.: 11 Cov.: 31

Gnomad AFR AF: 0.00243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00297

Gnomad ASJ AF: 0.00347

Gnomad EAS AF: 0.00745

Gnomad SAS AF: 0.00383

Gnomad FIN AF: 0.0251

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0131

Gnomad OTH AF: 0.00632

GnomAD3 exomes AF: 0.00979 AC: 1614 AN: 164858 Hom.: 16 AF XY: 0.0101 AC XY: 900 AN XY: 88864

Gnomad AFR exome AF: 0.00212

Gnomad AMR exome AF: 0.00288

Gnomad ASJ exome AF: 0.00557

Gnomad EAS exome AF: 0.00675

Gnomad SAS exome AF: 0.00226

Gnomad FIN exome AF: 0.0229

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0141 AC: 19170 AN: 1362612 Hom.: 172 Cov.: 62 AF XY: 0.0137 AC XY: 9140 AN XY: 666582

Gnomad4 AFR exome AF: 0.00155

Gnomad4 AMR exome AF: 0.00264

Gnomad4 ASJ exome AF: 0.00466

Gnomad4 EAS exome AF: 0.0254

Gnomad4 SAS exome AF: 0.00188

Gnomad4 FIN exome AF: 0.0204

Gnomad4 NFE exome AF: 0.0153

Gnomad4 OTH exome AF: 0.00915

GnomAD4 genome AF: 0.00909 AC: 1366 AN: 150224 Hom.: 11 Cov.: 31 AF XY: 0.00950 AC XY: 697 AN XY: 73364

Gnomad4 AFR AF: 0.00242

Gnomad4 AMR AF: 0.00297

Gnomad4 ASJ AF: 0.00347

Gnomad4 EAS AF: 0.00747

Gnomad4 SAS AF: 0.00383

Gnomad4 FIN AF: 0.0251

Gnomad4 NFE AF: 0.0131

Gnomad4 OTH AF: 0.00625

Alfa AF: 0.0113 Hom.: 14

Bravo AF: 0.00699

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00255 AC: 11

ESP6500EA AF: 0.0103 AC: 87

ExAC AF: 0.00887 AC: 1014

Asia WGS AF: 0.00549 AC: 19 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 25, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	SYNGAP1: PP2, BS1, BS2 -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 06, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 11, 2015	- -

Intellectual disability, autosomal dominant 5 Benign:2

Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Mental retardation, autosomal dominant 5, in Autosomal Dominant manner. The following ACMG Tag(s) were applied: BP4 => Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.). BS1 =>Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:19196676, 21237447). -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

May 19, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

SYNGAP1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 05, 2021

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	20
DANN	Benign	0.76
DEOGEN2	Benign	0.026	T;T;.;.;.;.;.;.
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.88	.;D;D;D;D;D;D;D
MetaRNN	Benign	0.0056	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.0	N;N;.;.;N;N;.;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-0.020	.;.;.;N;.;N;N;.
REVEL	Benign	0.10
Sift	Benign	0.58	.;.;.;T;.;T;T;.
Sift4G	Benign	0.41	.;T;.;T;T;T;T;.
Polyphen		0.0	B;B;.;.;B;B;.;.
Vest4		0.19, 0.21, 0.22, 0.19
MVP		0.082
MPC		1.4
ClinPred		0.0011	T
GERP RS		1.9
Varity_R		0.064
gMVP		0.35

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: rs191549504; hg19: chr6-33411673;