rs153478

Variant names:

• chr5-151259878-A-G
• rs153478
• NM_000405.5:c.205A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-151259878-A-G
• chr5-151259878-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000405.5(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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M69T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.75 (43324 hom., cov: 32)
  • Exomes 𝑓: 0.69 (353913 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.762
• Publications: 37 publications found

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 Gene-Disease associations (from GenCC):

• Tay-Sachs disease AB variant

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• 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 VariationId is 167151.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
GM2A	NM_000405.5	c.205A>G	p.Met69Val	missense_variant	Exon 2 of 4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3	c.205A>G	p.Met69Val	missense_variant	Exon 2 of 4		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000357164.4	c.205A>G	p.Met69Val	missense_variant	Exon 2 of 4	1	NM_000405.5	ENSP00000349687.3
GM2A	ENST00000523004.1	c.79A>G	p.Met27Val	missense_variant	Exon 1 of 2	1		ENSP00000430541.1
GM2A	ENST00000523466.5	c.250A>G	p.Met84Val	missense_variant	Exon 3 of 4	3		ENSP00000429100.1

Frequencies

GnomAD3 genomes AF: 0.747 AC: 113456 AN: 151980 Hom.: 43271 Cov.: 32

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

GnomAD2 exomes AF: 0.760 AC: 190631 AN: 250874 AF XY: 0.760

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 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.: 41 AF XY: 0.695 AC XY: 504642 AN XY: 725674

African (AFR) AF: 0.868 AC: 29038 AN: 33454

American (AMR) AF: 0.846 AC: 37803 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.720 AC: 18801 AN: 26122

East Asian (EAS) AF: 0.999 AC: 39659 AN: 39698

South Asian (SAS) AF: 0.911 AC: 78561 AN: 86220

European-Finnish (FIN) AF: 0.662 AC: 35341 AN: 53392

Middle Eastern (MID) AF: 0.792 AC: 4563 AN: 5760

European-Non Finnish (NFE) AF: 0.648 AC: 718352 AN: 1108868

Other (OTH) AF: 0.725 AC: 43684 AN: 60268

GnomAD4 genome AF: 0.747 AC: 113568 AN: 152098 Hom.: 43324 Cov.: 32 AF XY: 0.751 AC XY: 55831 AN XY: 74348

African (AFR) AF: 0.857 AC: 35583 AN: 41514

American (AMR) AF: 0.770 AC: 11763 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.709 AC: 2461 AN: 3472

East Asian (EAS) AF: 0.999 AC: 5173 AN: 5178

South Asian (SAS) AF: 0.920 AC: 4437 AN: 4822

European-Finnish (FIN) AF: 0.654 AC: 6908 AN: 10566

Middle Eastern (MID) AF: 0.803 AC: 236 AN: 294

European-Non Finnish (NFE) AF: 0.658 AC: 44753 AN: 67962

Other (OTH) AF: 0.747 AC: 1572 AN: 2104

Alfa AF: 0.703 Hom.: 81962

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

Submissions by phenotype

Tay-Sachs disease, variant AB Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 20, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.56	T
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	N
LIST_S2	Benign	0.093	T;T
MetaRNN	Benign	7.7e-7	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.90	.;N
PhyloP100		0.76
PrimateAI	Benign	0.31	T
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	T
GERP RS		-2.4
PromoterAI		0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.10
gMVP		0.58
Mutation Taster		=96/4	polymorphism (auto)

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

Other links and lift over

dbSNP: rs153478; hg19: chr5-150639439; COSMIC: COSV100852054;