rs150153477

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_006772.3(SYNGAP1):c.1776A>G(p.Ser592Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,613,806 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00096 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 8 hom. )

Consequence

SYNGAP1
NM_006772.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -3.41

Publications

0 publications found

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 was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 6-33440828-A-G is Benign according to our data. Variant chr6-33440828-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 240705.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.41 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000961 (146/151926) while in subpopulation SAS AF = 0.00457 (22/4814). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 146 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.1776A>G	p.Ser592Ser	synonymous_variant	Exon 11 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYNGAP1	ENST00000646630.1 link	c.1776A>G	p.Ser592Ser	synonymous_variant	Exon 11 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1 link	c.1776A>G	p.Ser592Ser	synonymous_variant	Exon 11 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7 link	c.1776A>G	p.Ser592Ser	synonymous_variant	Exon 11 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7 link	c.1776A>G	p.Ser592Ser	synonymous_variant	Exon 11 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1 link	c.1599A>G	p.Ser533Ser	synonymous_variant	Exon 9 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes

AF:

0.000962

AC:

146

AN:

151808

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000218

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000919

Gnomad ASJ

AF:

0.00403

Gnomad EAS

AF:

0.000386

Gnomad SAS

AF:

0.00457

Gnomad FIN

AF:

0.000190

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00106

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00160

AC:

402

AN:

251420

AF XY:

0.00191

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00268

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00135

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00111

AC:

1629

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00125

AC XY:

911

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.000478

AC:

AN:

33480

American (AMR)

AF:

0.00145

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00268

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00495

AC:

427

AN:

86256

European-Finnish (FIN)

AF:

0.0000562

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.0116

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.000790

AC:

879

AN:

1112006

Other (OTH)

AF:

0.00166

AC:

100

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

127

254

380

507

634

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000961

AC:

146

AN:

151926

Hom.:

Cov.:

AF XY:

0.000915

AC XY:

AN XY:

74280

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41408

American (AMR)

AF:

0.000917

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00403

AC:

AN:

3470

East Asian (EAS)

AF:

0.000387

AC:

AN:

5172

South Asian (SAS)

AF:

0.00457

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000190

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.0170

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00106

AC:

AN:

67940

Other (OTH)

AF:

0.00285

AC:

AN:

2104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00138

Hom.:

Bravo

AF:

0.000948

Asia WGS

AF:

0.00404

AC:

AN:

3478

EpiCase

AF:

0.00207

EpiControl

AF:

0.00284

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SYNGAP1: BP4, BP7 -

not specified

Benign:2

Dec 30, 2016

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 27, 2024

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 15, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely 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

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

SYNGAP1-related disorder

Benign:1

Aug 30, 2021

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

7.1

(source)

DANN

Benign

0.62

PhyloP100

-3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over