rs764952741

Positions:

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_ModerateBP6_Very_StrongBS2

The NM_006772.3(SYNGAP1):c.3308G>A(p.Arg1103His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000203 in 1,529,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1103C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000022 ( 0 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 3.15

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 -13 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=0.21439043).

BP6

Variant 6-33443860-G-A is Benign according to our data. Variant chr6-33443860-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 577408.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SYNGAP1	NM_006772.3 linkuse as main transcript	c.3308G>A	p.Arg1103His	missense_variant	15/19	ENST00000646630.1
SYNGAP1-AS1	NR_174954.1 linkuse as main transcript	n.329+2746C>T		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.3308G>A	p.Arg1103His	missense_variant	15/19		NM_006772.3	P1	Q96PV0-1
SYNGAP1-AS1	ENST00000630418.1 linkuse as main transcript	n.377+2746C>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151872

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000225

AC:

AN:

177710

Hom.:

AF XY:

0.0000314

AC XY:

AN XY:

95420

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000119

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000247

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000218

AC:

AN:

1377530

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

675182

show subpopulations

Gnomad4 AFR exome

AF:

0.0000323

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000257

Gnomad4 SAS exome

AF:

0.0000411

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000215

Gnomad4 OTH exome

AF:

0.0000176

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151872

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74172

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000144

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000170

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 5

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 27, 2023	- -
Uncertain significance, no assertion criteria provided	clinical testing	Zotz-Klimas Genetics Lab, MVZ Zotz Klimas	Nov 02, 2023	- -

not provided

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jun 01, 2022

SYNGAP1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.10

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.77

LIST_S2

Uncertain

0.95

.;D;D;D;D;D;D;D

M_CAP

Benign

0.018

MetaRNN

Benign

0.21

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

M;M;.;.;M;M;.;.

MutationTaster

Benign

0.64

N;N;N;N

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-1.8

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

REVEL

Benign

0.12

Sift

Uncertain

0.012

.;.;.;D;.;D;D;.

Sift4G

Benign

0.15

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

Polyphen

1.0

D;D;.;.;D;D;.;.

Vest4

0.37, 0.30, 0.33, 0.29

MVP

0.37

MPC

1.4

ClinPred

0.33

GERP RS

3.5

Varity_R

0.072

gMVP

0.22

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