rs1048723

Variant names:

• chr5-151267451-A-G
• rs1048723
• NM_000405.5:c.582A>G

Your query was ambiguous. Multiple possible variants found:

• chr5-151267451-A-G
• chr5-151267451-A-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000405.5(GM2A):​c.582A>G​(p.Ter194Ter) variant causes a stop retained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 1,613,664 control chromosomes in the GnomAD database, including 63,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.25 (5159 hom., cov: 32)
  • Exomes 𝑓: 0.28 (58440 hom.)
• Consequence: GM2A NM_000405.5 stop_retained
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.644
• Publications: 19 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 5-151267451-A-G is Benign according to our data. Variant chr5-151267451-A-G is described in ClinVar as Benign. ClinVar VariationId is 167152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.644 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GM2A	NM_000405.5	c.582A>G	p.Ter194Ter	stop_retained_variant	Exon 4 of 4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3	c.413-41A>G		intron_variant	Intron 3 of 3		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000357164.4	c.582A>G	p.Ter194Ter	stop_retained_variant	Exon 4 of 4	1	NM_000405.5	ENSP00000349687.3
GM2A	ENST00000523004.1	c.*526A>G		downstream_gene_variant		1		ENSP00000430541.1

Frequencies

GnomAD3 genomes AF: 0.247 AC: 37477 AN: 152004 Hom.: 5153 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.216

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.329

Gnomad EAS AF: 0.276

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.239

Gnomad MID AF: 0.278

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.278

GnomAD2 exomes AF: 0.303 AC: 75980 AN: 251122 AF XY: 0.300

Gnomad AFR exome AF: 0.130

Gnomad AMR exome AF: 0.506

Gnomad ASJ exome AF: 0.338

Gnomad EAS exome AF: 0.261

Gnomad FIN exome AF: 0.248

Gnomad NFE exome AF: 0.272

Gnomad OTH exome AF: 0.311

GnomAD4 exome AF: 0.277 AC: 404436 AN: 1461542 Hom.: 58440 Cov.: 37 AF XY: 0.278 AC XY: 202236 AN XY: 727086

African (AFR) AF: 0.132 AC: 4414 AN: 33480

American (AMR) AF: 0.495 AC: 22145 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.335 AC: 8759 AN: 26134

East Asian (EAS) AF: 0.278 AC: 11017 AN: 39696

South Asian (SAS) AF: 0.329 AC: 28411 AN: 86242

European-Finnish (FIN) AF: 0.247 AC: 13194 AN: 53404

Middle Eastern (MID) AF: 0.333 AC: 1921 AN: 5766

European-Non Finnish (NFE) AF: 0.268 AC: 297909 AN: 1111730

Other (OTH) AF: 0.276 AC: 16666 AN: 60390

GnomAD4 genome AF: 0.246 AC: 37496 AN: 152122 Hom.: 5159 Cov.: 32 AF XY: 0.251 AC XY: 18648 AN XY: 74374

African (AFR) AF: 0.132 AC: 5489 AN: 41512

American (AMR) AF: 0.390 AC: 5966 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.329 AC: 1140 AN: 3470

East Asian (EAS) AF: 0.276 AC: 1428 AN: 5170

South Asian (SAS) AF: 0.339 AC: 1633 AN: 4824

European-Finnish (FIN) AF: 0.239 AC: 2533 AN: 10586

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18444 AN: 67964

Other (OTH) AF: 0.278 AC: 587 AN: 2112

Alfa AF: 0.275 Hom.: 5309

Bravo AF: 0.255

Asia WGS AF: 0.269 AC: 933 AN: 3478

EpiCase AF: 0.281

EpiControl AF: 0.287

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

Feb 04, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

Oct 26, 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
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.6
DANN	Benign	0.58
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1048723; hg19: chr5-150647012; COSMIC: COSV64095746; COSMIC: COSV64095746;