rs1048723

Positions:

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

Variant summary

Our verdict is Benign. Variant got -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

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]

ACMG classification

Verdict is Benign. Variant got -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 id is 167152.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-151267451-A-G is described in Lovd as [Benign].
• 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/exons	MANE	Protein	UniProt
GM2A	NM_000405.5	c.582A>G	p.Ter194Ter	stop_retained_variant	4/4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3	c.413-41A>G		intron_variant			NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000357164.4	c.582A>G	p.Ter194Ter	stop_retained_variant	4/4	1	NM_000405.5	ENSP00000349687.3

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

GnomAD3 exomes AF: 0.303 AC: 75980 AN: 251122 Hom.: 12724 AF XY: 0.300 AC XY: 40705 AN XY: 135722

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 SAS exome AF: 0.327

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

Gnomad4 AFR exome AF: 0.132

Gnomad4 AMR exome AF: 0.495

Gnomad4 ASJ exome AF: 0.335

Gnomad4 EAS exome AF: 0.278

Gnomad4 SAS exome AF: 0.329

Gnomad4 FIN exome AF: 0.247

Gnomad4 NFE exome AF: 0.268

Gnomad4 OTH exome AF: 0.276

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

Gnomad4 AFR AF: 0.132

Gnomad4 AMR AF: 0.390

Gnomad4 ASJ AF: 0.329

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.239

Gnomad4 NFE AF: 0.271

Gnomad4 OTH AF: 0.278

Alfa AF: 0.275 Hom.: 4004

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

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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	Eurofins Ntd Llc (ga)	Feb 04, 2014	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:1

Benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Oct 26, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.6
DANN	Benign	0.58

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

Publications

LitVar

Other links and lift over

dbSNP: rs1048723; hg19: chr5-150647012; COSMIC: COSV64095746; COSMIC: COSV64095746;