rs191549504

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1115L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0091 ( 11 hom., cov: 31)

Exomes 𝑓: 0.014 ( 172 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.654

Publications

7 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 -20 ACMG points.

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 VariationId is 130530.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 1366 AD,Unknown gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.3344T>C	p.Ile1115Thr	missense_variant	Exon 15 of 19	ENST00000646630.1	NP_006763.2	Q96PV0-1A0A1U9X8L0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SYNGAP1	ENST00000646630.1 link	c.3344T>C	p.Ile1115Thr	missense_variant	Exon 15 of 19		NM_006772.3	ENSP00000496007.1	Q96PV0-1
SYNGAP1	ENST00000644458.1 link	c.3344T>C	p.Ile1115Thr	missense_variant	Exon 15 of 19			ENSP00000495541.1	A0A2R8Y6T2
SYNGAP1	ENST00000449372.7 link	c.3302T>C	p.Ile1101Thr	missense_variant	Exon 14 of 18	5		ENSP00000416519.4	B7ZCA0
SYNGAP1	ENST00000418600.7 link	c.3344T>C	p.Ile1115Thr	missense_variant	Exon 15 of 19	5		ENSP00000403636.3	Q96PV0-2
SYNGAP1	ENST00000645250.1 link	c.3167T>C	p.Ile1056Thr	missense_variant	Exon 13 of 17			ENSP00000494861.1	A0A2R8YDS2

Frequencies

GnomAD3 genomes

AF:

0.00910

AC:

1366

AN:

150108

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00979

AC:

1614

AN:

164858

AF XY:

0.0101

show subpopulations

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 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.:

AF XY:

0.0137

AC XY:

9140

AN XY:

666582

show subpopulations

African (AFR)

AF:

0.00155

AC:

AN:

30304

American (AMR)

AF:

0.00264

AC:

AN:

29910

Ashkenazi Jewish (ASJ)

AF:

0.00466

AC:

AN:

19956

East Asian (EAS)

AF:

0.0254

AC:

980

AN:

38656

South Asian (SAS)

AF:

0.00188

AC:

132

AN:

70362

European-Finnish (FIN)

AF:

0.0204

AC:

991

AN:

48510

Middle Eastern (MID)

AF:

0.00171

AC:

AN:

5260

European-Non Finnish (NFE)

AF:

0.0153

AC:

16326

AN:

1063616

Other (OTH)

AF:

0.00915

AC:

513

AN:

56038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1086

2172

3258

4344

5430

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

664

1328

1992

2656

3320

<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:

0.00909

AC:

1366

AN:

150224

Hom.:

Cov.:

AF XY:

0.00950

AC XY:

697

AN XY:

73364

show subpopulations

African (AFR)

AF:

0.00242

AC:

AN:

40828

American (AMR)

AF:

0.00297

AC:

AN:

15172

Ashkenazi Jewish (ASJ)

AF:

0.00347

AC:

AN:

3456

East Asian (EAS)

AF:

0.00747

AC:

AN:

5084

South Asian (SAS)

AF:

0.00383

AC:

AN:

4700

European-Finnish (FIN)

AF:

0.0251

AC:

259

AN:

10310

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.0131

AC:

882

AN:

67402

Other (OTH)

AF:

0.00625

AC:

AN:

2080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

133

200

266

333

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0113

Hom.:

Bravo

AF:

0.00699

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00255

AC:

ESP6500EA

AF:

0.0103

AC:

ExAC

AF:

0.00887

AC:

1014

Asia WGS

AF:

0.00549

AC:

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Jul 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Aug 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

SYNGAP1: PP2, BS1, BS2 -

not specified

Benign:2

Jun 11, 2015

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 06, 2020

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Intellectual disability, autosomal dominant 5

Benign:2

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:curation

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). -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 19, 2016

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 05, 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

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.76

DEOGEN2

Benign

0.026

T;T;.;.;.;.;.;.

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.38

FATHMM_MKL

Uncertain

0.86

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

MutationAssessor

Benign

0.0

N;N;.;.;N;N;.;.

PhyloP100

0.65

PrimateAI

Uncertain

0.78

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

GERP RS

1.9

Varity_R

0.064

gMVP

0.35

Mutation Taster

=99/1

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