NM_006772.3:c.707C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 4P and 12B. PM1PP2PP3BP6_Very_StrongBS2

The NM_006772.3(SYNGAP1):c.707C>T(p.Ala236Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 7.91

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM1

In a domain PH (size 101) in uniprot entity SYGP1_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in NM_006772.3

PP2

Missense variant in the SYNGAP1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 56 curated pathogenic missense variants (we use a threshold of 10). The gene has 112 curated benign missense variants. Gene score misZ: 5.6047 (above the threshold of 3.09). Trascript score misZ: 7.6762 (above the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant non-syndromic intellectual disability, complex neurodevelopmental disorder, intellectual disability, autosomal dominant 5, SYNGAP1-related developmental and epileptic encephalopathy, myoclonic-astatic epilepsy.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.822

BP6

Variant 6-33435558-C-T is Benign according to our data. Variant chr6-33435558-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 469162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.707C>T	p.Ala236Val	missense_variant	Exon 7 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.707C>T	p.Ala236Val	missense_variant	Exon 7 of 19		NM_006772.3	ENSP00000496007.1	Q96PV0-1
SYNGAP1	ENST00000644458.1 link	c.707C>T	p.Ala236Val	missense_variant	Exon 7 of 19			ENSP00000495541.1	A0A2R8Y6T2
SYNGAP1	ENST00000449372.7 link	c.707C>T	p.Ala236Val	missense_variant	Exon 7 of 18	5		ENSP00000416519.4	B7ZCA0
SYNGAP1	ENST00000418600.7 link	c.707C>T	p.Ala236Val	missense_variant	Exon 7 of 19	5		ENSP00000403636.3	Q96PV0-2
SYNGAP1	ENST00000645250.1 link	c.530C>T	p.Ala177Val	missense_variant	Exon 5 of 17			ENSP00000494861.1	A0A2R8YDS2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251448

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135910

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000879

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 5

Benign:1

Apr 07, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Feb 25, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.27

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.60

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

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.46

MetaRNN

Pathogenic

0.82

D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.82

MutationAssessor

Uncertain

2.7

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

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.5

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

REVEL

Pathogenic

0.78

Sift

Uncertain

0.0050

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.98

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

Vest4

0.58, 0.57, 0.53, 0.52

MutPred

0.37

Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);Loss of helix (P = 0.0558);.;.;

MVP

0.82

MPC

1.4

ClinPred

0.92

GERP RS

4.6

Varity_R

0.27

gMVP

0.83

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