dbSNP rs1485749468: SYNGAP1:p.Lys642Thr (chr6-33441184-A-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP5_Moderate

The NM_006772.3(SYNGAP1):c.1925A>C(p.Lys642Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 31)

Consequence

SYNGAP1
NM_006772.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.30

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 6-33441184-A-C is Pathogenic according to our data. Variant chr6-33441184-A-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 437411.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SYNGAP1	NM_006772.3 link	c.1925A>C	p.Lys642Thr	missense_variant	Exon 12 of 19	ENST00000646630.1	NP_006763.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
SYNGAP1	ENST00000646630.1 link	c.1925A>C	p.Lys642Thr	missense_variant	Exon 12 of 19		NM_006772.3	ENSP00000496007.1
SYNGAP1	ENST00000644458.1 link	c.1925A>C	p.Lys642Thr	missense_variant	Exon 12 of 19			ENSP00000495541.1
SYNGAP1	ENST00000449372.7 link	c.1925A>C	p.Lys642Thr	missense_variant	Exon 12 of 18	5		ENSP00000416519.4
SYNGAP1	ENST00000418600.7 link	c.1925A>C	p.Lys642Thr	missense_variant	Exon 12 of 19	5		ENSP00000403636.3
SYNGAP1	ENST00000645250.1 link	c.1748A>C	p.Lys583Thr	missense_variant	Exon 10 of 17			ENSP00000494861.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Intellectual disability, autosomal dominant 5

Pathogenic:1

Jan 12, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.81

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

Eigen

Uncertain

0.57

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

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

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.73

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

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.8

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

PhyloP100

9.3

PrimateAI

Pathogenic

0.83

PROVEAN

Pathogenic

-5.7

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

REVEL

Uncertain

0.48

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.55

P;P;.;.;P;P;.;.

Vest4

0.81, 0.92, 0.77, 0.86

MutPred

0.44

Loss of ubiquitination at K642 (P = 0.0092);Loss of ubiquitination at K642 (P = 0.0092);Loss of ubiquitination at K642 (P = 0.0092);Loss of ubiquitination at K642 (P = 0.0092);Loss of ubiquitination at K642 (P = 0.0092);Loss of ubiquitination at K642 (P = 0.0092);.;.;

MVP

0.73

MPC

1.6

ClinPred

1.0

GERP RS

4.8

Varity_R

0.51

gMVP

0.96

Mutation Taster

=3/97

disease causing (ClinVar)

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over