rs153478

Positions:

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000357164.4(GM2A):c.205A>G(p.Met69Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.695 in 1,610,570 control chromosomes in the GnomAD database, including 397,237 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 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. M69A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.75 ( 43324 hom., cov: 32)

Exomes 𝑓: 0.69 ( 353913 hom. )

Consequence

GM2A
ENST00000357164.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.762

Variant links:

Genes affected

GM2A (HGNC:4367): (ganglioside GM2 activator) This gene encodes a small glycolipid transport protein which acts as a substrate specific co-factor for the lysosomal enzyme beta-hexosaminidase A. Beta-hexosaminidase A, together with GM2 ganglioside activator, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene result in GM2-gangliosidosis type AB or the AB variant of Tay-Sachs disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2009]

GM2A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Ganglioside GM2 activator (size 161) in uniprot entity SAP3_HUMAN there are 5 pathogenic changes around while only 2 benign (71%) in ENST00000357164.4

BP4

Computational evidence support a benign effect (MetaRNN=7.680591E-7).

BP6

Variant 5-151259878-A-G is Benign according to our data. Variant chr5-151259878-A-G is described in ClinVar as [Benign]. Clinvar id is 167151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151259878-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GM2A	NM_000405.5 linkuse as main transcript	c.205A>G	p.Met69Val	missense_variant	2/4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3 linkuse as main transcript	c.205A>G	p.Met69Val	missense_variant	2/4		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
GM2A	ENST00000357164.4 linkuse as main transcript	c.205A>G	p.Met69Val	missense_variant	2/4	1	NM_000405.5	ENSP00000349687	P1
GM2A	ENST00000523004.1 linkuse as main transcript	c.82A>G	p.Met28Val	missense_variant	1/2	1		ENSP00000430541
GM2A	ENST00000523466.5 linkuse as main transcript	c.250A>G	p.Met84Val	missense_variant	3/4	3		ENSP00000429100

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113456

AN:

151980

Hom.:

43271

Cov.:

show subpopulations

Gnomad AFR

AF:

0.857

Gnomad AMI

AF:

0.749

Gnomad AMR

AF:

0.770

Gnomad ASJ

AF:

0.709

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.921

Gnomad FIN

AF:

0.654

Gnomad MID

AF:

0.804

Gnomad NFE

AF:

0.658

Gnomad OTH

AF:

0.744

GnomAD3 exomes

AF:

0.760

AC:

190631

AN:

250874

Hom.:

74298

AF XY:

0.760

AC XY:

102975

AN XY:

135582

show subpopulations

Gnomad AFR exome

AF:

0.860

Gnomad AMR exome

AF:

0.850

Gnomad ASJ exome

AF:

0.725

Gnomad EAS exome

AF:

0.999

Gnomad SAS exome

AF:

0.913

Gnomad FIN exome

AF:

0.665

Gnomad NFE exome

AF:

0.661

Gnomad OTH exome

AF:

0.731

GnomAD4 exome

AF:

0.690

AC:

1005802

AN:

1458472

Hom.:

353913

Cov.:

AF XY:

0.695

AC XY:

504642

AN XY:

725674

show subpopulations

Gnomad4 AFR exome

AF:

0.868

Gnomad4 AMR exome

AF:

0.846

Gnomad4 ASJ exome

AF:

0.720

Gnomad4 EAS exome

AF:

0.999

Gnomad4 SAS exome

AF:

0.911

Gnomad4 FIN exome

AF:

0.662

Gnomad4 NFE exome

AF:

0.648

Gnomad4 OTH exome

AF:

0.725

GnomAD4 genome

AF:

0.747

AC:

113568

AN:

152098

Hom.:

43324

Cov.:

AF XY:

0.751

AC XY:

55831

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.857

Gnomad4 AMR

AF:

0.770

Gnomad4 ASJ

AF:

0.709

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.920

Gnomad4 FIN

AF:

0.654

Gnomad4 NFE

AF:

0.658

Gnomad4 OTH

AF:

0.747

Alfa

AF:

0.691

Hom.:

56550

Bravo

AF:

0.761

TwinsUK

AF:

0.633

AC:

2349

ALSPAC

AF:

0.644

AC:

2481

ESP6500AA

AF:

0.851

AC:

3750

ESP6500EA

AF:

0.657

AC:

5652

ExAC

AF:

0.762

AC:

92523

Asia WGS

AF:

0.949

AC:

3301

AN:

3478

EpiCase

AF:

0.660

EpiControl

AF:

0.670

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Tay-Sachs disease, variant AB

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2014	- -

not provided

Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 20, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.44

CADD

Benign

1.8

DANN

Benign

0.34

DEOGEN2

Benign

0.083

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.093

T;T

MetaRNN

Benign

7.7e-7

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.90

.;N

MutationTaster

Benign

1.0

PrimateAI

Benign

0.31

PROVEAN

Benign

0.28

N;N

REVEL

Benign

0.23

Sift

Benign

0.29

T;T

Sift4G

Benign

0.24

T;T

Polyphen

0.0

.;B

Vest4

0.010

MPC

0.069

ClinPred

0.0095

GERP RS

-2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.10

gMVP

0.58

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