rs587780471

Positions:

Variant summary

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

The NM_006772.3(SYNGAP1):c.1536A>G(p.Glu512=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0282 in 1,613,972 control chromosomes in the GnomAD database, including 1,883 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.069 ( 802 hom., cov: 32)

Exomes 𝑓: 0.024 ( 1081 hom. )

Consequence

SYNGAP1
NM_006772.3 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.214

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=-0.68).

BP6

Variant 6-33438779-A-G is Benign according to our data. Variant chr6-33438779-A-G is described in ClinVar as [Benign]. Clinvar id is 130523.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-33438779-A-G is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.214 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.184 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 linkuse as main transcript	c.1536A>G	p.Glu512=	synonymous_variant	10/19	ENST00000646630.1	NP_006763.2
SYNGAP1-AS1	NR_174954.1 linkuse as main transcript	n.330-1298T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SYNGAP1	ENST00000646630.1 linkuse as main transcript	c.1536A>G	p.Glu512=	synonymous_variant	10/19		NM_006772.3	ENSP00000496007	P1	Q96PV0-1
SYNGAP1-AS1	ENST00000630418.1 linkuse as main transcript	n.378-1298T>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0688

AC:

10460

AN:

151976

Hom.:

798

Cov.:

show subpopulations

Gnomad AFR

AF:

0.187

Gnomad AMI

AF:

0.0471

Gnomad AMR

AF:

0.0445

Gnomad ASJ

AF:

0.0461

Gnomad EAS

AF:

0.0148

Gnomad SAS

AF:

0.0237

Gnomad FIN

AF:

0.00349

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0697

GnomAD3 exomes

AF:

0.0347

AC:

8731

AN:

251478

Hom.:

404

AF XY:

0.0323

AC XY:

4393

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.193

Gnomad AMR exome

AF:

0.0326

Gnomad ASJ exome

AF:

0.0429

Gnomad EAS exome

AF:

0.0165

Gnomad SAS exome

AF:

0.0309

Gnomad FIN exome

AF:

0.00471

Gnomad NFE exome

AF:

0.0215

Gnomad OTH exome

AF:

0.0378

GnomAD4 exome

AF:

0.0240

AC:

35075

AN:

1461878

Hom.:

1081

Cov.:

AF XY:

0.0238

AC XY:

17343

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.192

Gnomad4 AMR exome

AF:

0.0352

Gnomad4 ASJ exome

AF:

0.0447

Gnomad4 EAS exome

AF:

0.00982

Gnomad4 SAS exome

AF:

0.0307

Gnomad4 FIN exome

AF:

0.00492

Gnomad4 NFE exome

AF:

0.0179

Gnomad4 OTH exome

AF:

0.0360

GnomAD4 genome

AF:

0.0689

AC:

10482

AN:

152094

Hom.:

802

Cov.:

AF XY:

0.0671

AC XY:

4988

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.187

Gnomad4 AMR

AF:

0.0445

Gnomad4 ASJ

AF:

0.0461

Gnomad4 EAS

AF:

0.0145

Gnomad4 SAS

AF:

0.0237

Gnomad4 FIN

AF:

0.00349

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0690

Alfa

AF:

0.0438

Hom.:

265

Bravo

AF:

0.0796

Asia WGS

AF:

0.0330

AC:

114

AN:

3478

EpiCase

AF:

0.0270

EpiControl

AF:

0.0285

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

-0.68

CADD

Benign

5.3

DANN

Benign

0.69

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