6-33443522-C-T

Position:

chr6-33443522-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_006772.3(SYNGAP1):c.2970C>T(p.Ser990=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,614,142 control chromosomes in the GnomAD database, including 1,166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.054 ( 541 hom., cov: 32)

Exomes 𝑓: 0.016 ( 625 hom. )

Consequence

SYNGAP1
NM_006772.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.340

Variant links:

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 links:

SYNGAP1-AS1 (HGNC:53831): (SYNGAP1 antisense RNA 1)

SYNGAP1-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 6-33443522-C-T is Benign according to our data. Variant chr6-33443522-C-T is described in ClinVar as [Benign]. Clinvar id is 130529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33443522-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-0.34 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.153 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3 linkuse as main transcript	c.2970C>T	p.Ser990=	synonymous_variant	15/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1 linkuse as main transcript	n.329+3084G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SYNGAP1	ENST00000646630.1 linkuse as main transcript	c.2970C>T	p.Ser990=	synonymous_variant	15/19		NM_006772.3	P1	Q96PV0-1
SYNGAP1-AS1	ENST00000630418.1 linkuse as main transcript	n.377+3084G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0542

AC:

8253

AN:

152156

Hom.:

537

Cov.:

show subpopulations

Gnomad AFR

AF:

0.156

Gnomad AMI

AF:

0.0340

Gnomad AMR

AF:

0.0325

Gnomad ASJ

AF:

0.0285

Gnomad EAS

AF:

0.00751

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0132

Gnomad OTH

AF:

0.0593

GnomAD3 exomes

AF:

0.0239

AC:

5998

AN:

251362

Hom.:

260

AF XY:

0.0211

AC XY:

2872

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.162

Gnomad AMR exome

AF:

0.0247

Gnomad ASJ exome

AF:

0.0244

Gnomad EAS exome

AF:

0.00527

Gnomad SAS exome

AF:

0.0164

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.0129

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0159

AC:

23227

AN:

1461868

Hom.:

625

Cov.:

AF XY:

0.0155

AC XY:

11296

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.159

Gnomad4 AMR exome

AF:

0.0263

Gnomad4 ASJ exome

AF:

0.0261

Gnomad4 EAS exome

AF:

0.00310

Gnomad4 SAS exome

AF:

0.0166

Gnomad4 FIN exome

AF:

0.00258

Gnomad4 NFE exome

AF:

0.0111

Gnomad4 OTH exome

AF:

0.0266

GnomAD4 genome

AF:

0.0543

AC:

8275

AN:

152274

Hom.:

541

Cov.:

AF XY:

0.0519

AC XY:

3861

AN XY:

74452

show subpopulations

Gnomad4 AFR

AF:

0.157

Gnomad4 AMR

AF:

0.0325

Gnomad4 ASJ

AF:

0.0285

Gnomad4 EAS

AF:

0.00714

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.00151

Gnomad4 NFE

AF:

0.0132

Gnomad4 OTH

AF:

0.0587

Alfa

AF:

0.0360

Hom.:

164

Bravo

AF:

0.0630

Asia WGS

AF:

0.0270

AC:

AN:

3478

EpiCase

AF:

0.0157

EpiControl

AF:

0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 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. -

Intellectual disability, autosomal dominant 5

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 17, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.71

CADD

Benign

1.1

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over