rs153477

Positions:

chr5-151259848-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000405.5(GM2A):c.175A>G(p.Ile59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,609,530 control chromosomes in the GnomAD database, including 326,470 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 (★★).

Frequency

Genomes: 𝑓 0.63 ( 30424 hom., cov: 33)

Exomes 𝑓: 0.63 ( 296046 hom. )

Consequence

GM2A
NM_000405.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.864

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.319748E-6).

BP6

Variant 5-151259848-A-G is Benign according to our data. Variant chr5-151259848-A-G is described in ClinVar as [Benign]. Clinvar id is 167150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151259848-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GM2A	NM_000405.5 link	c.175A>G	p.Ile59Val	missense_variant	2/4	ENST00000357164.4	NP_000396.2	P17900
GM2A	NM_001167607.3 link	c.175A>G	p.Ile59Val	missense_variant	2/4		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GM2A	ENST00000357164.4 link	c.175A>G	p.Ile59Val	missense_variant	2/4	1	NM_000405.5	ENSP00000349687.3	P17900
GM2A	ENST00000523004.1 link	c.49A>G	p.Ile17Val	missense_variant	1/2	1		ENSP00000430541.1	H0YBY3
GM2A	ENST00000523466.5 link	c.220A>G	p.Ile74Val	missense_variant	3/4	3		ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes

AF:

0.629

AC:

95647

AN:

151956

Hom.:

30398

Cov.:

show subpopulations

Gnomad AFR

AF:

0.585

Gnomad AMI

AF:

0.738

Gnomad AMR

AF:

0.695

Gnomad ASJ

AF:

0.680

Gnomad EAS

AF:

0.648

Gnomad SAS

AF:

0.761

Gnomad FIN

AF:

0.614

Gnomad MID

AF:

0.756

Gnomad NFE

AF:

0.628

Gnomad OTH

AF:

0.657

GnomAD3 exomes

AF:

0.667

AC:

167416

AN:

251014

Hom.:

56479

AF XY:

0.670

AC XY:

90852

AN XY:

135654

show subpopulations

Gnomad AFR exome

AF:

0.581

Gnomad AMR exome

AF:

0.777

Gnomad ASJ exome

AF:

0.696

Gnomad EAS exome

AF:

0.640

Gnomad SAS exome

AF:

0.766

Gnomad FIN exome

AF:

0.621

Gnomad NFE exome

AF:

0.629

Gnomad OTH exome

AF:

0.673

GnomAD4 exome

AF:

0.635

AC:

925008

AN:

1457456

Hom.:

296046

Cov.:

AF XY:

0.639

AC XY:

463362

AN XY:

725224

show subpopulations

Gnomad4 AFR exome

AF:

0.592

Gnomad4 AMR exome

AF:

0.773

Gnomad4 ASJ exome

AF:

0.690

Gnomad4 EAS exome

AF:

0.659

Gnomad4 SAS exome

AF:

0.768

Gnomad4 FIN exome

AF:

0.618

Gnomad4 NFE exome

AF:

0.617

Gnomad4 OTH exome

AF:

0.648

GnomAD4 genome

AF:

0.629

AC:

95729

AN:

152074

Hom.:

30424

Cov.:

AF XY:

0.631

AC XY:

46943

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.585

Gnomad4 AMR

AF:

0.696

Gnomad4 ASJ

AF:

0.680

Gnomad4 EAS

AF:

0.648

Gnomad4 SAS

AF:

0.761

Gnomad4 FIN

AF:

0.614

Gnomad4 NFE

AF:

0.628

Gnomad4 OTH

AF:

0.657

Alfa

AF:

0.633

Hom.:

64871

Bravo

AF:

0.636

TwinsUK

AF:

0.608

AC:

2253

ALSPAC

AF:

0.612

AC:

2359

ESP6500AA

AF:

0.574

AC:

2528

ESP6500EA

AF:

0.627

AC:

5388

ExAC

AF:

0.665

AC:

80704

Asia WGS

AF:

0.707

AC:

2460

AN:

3478

EpiCase

AF:

0.629

EpiControl

AF:

0.640

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	Illumina Laboratory Services, Illumina	Jan 12, 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. -
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	- -

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

0.059

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.49

CADD

Benign

0.075

DANN

Benign

0.28

DEOGEN2

Benign

0.084

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.032

T;T

MetaRNN

Benign

0.0000013

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

-1.9

.;N

PrimateAI

Benign

0.24

PROVEAN

Benign

0.62

N;N

REVEL

Benign

0.13

Sift

Benign

0.42

T;T

Sift4G

Benign

0.48

T;T

Polyphen

0.0

.;B

Vest4

0.010

MPC

0.058

ClinPred

0.0040

GERP RS

-0.55

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.072

gMVP

0.44

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