rs1048719

Variant names:

• chr5-151253271-G-A
• rs1048719
• NM_000405.5:c.55G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-151253271-G-A
• chr5-151253271-G-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.55G>A​(p.Ala19Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0402 in 1,613,552 control chromosomes in the GnomAD database, including 2,409 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. A19G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.040 (261 hom., cov: 32)
  • Exomes 𝑓: 0.040 (2148 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.100
• Publications: 18 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=0.0011257827).
• BP6: Variant 5-151253271-G-A is Benign according to our data. Variant chr5-151253271-G-A is described in ClinVar as Benign. ClinVar VariationId is 256030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.192 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GM2A	NM_000405.5	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 4	ENST00000357164.4	NP_000396.2
GM2A	NM_001167607.3	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 4		NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000357164.4	c.55G>A	p.Ala19Thr	missense_variant	Exon 1 of 4	1	NM_000405.5	ENSP00000349687.3
GM2A	ENST00000523466.5	c.127-6484G>A		intron_variant	Intron 2 of 3	3		ENSP00000429100.1

Frequencies

GnomAD3 genomes AF: 0.0399 AC: 6070 AN: 152152 Hom.: 263 Cov.: 32

Gnomad AFR AF: 0.0211

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.0812

Gnomad FIN AF: 0.0383

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0292

Gnomad OTH AF: 0.0373

GnomAD2 exomes AF: 0.0607 AC: 15228 AN: 251070 AF XY: 0.0591

Gnomad AFR exome AF: 0.0225

Gnomad AMR exome AF: 0.118

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.197

Gnomad FIN exome AF: 0.0418

Gnomad NFE exome AF: 0.0299

Gnomad OTH exome AF: 0.0417

GnomAD4 exome AF: 0.0402 AC: 58768 AN: 1461282 Hom.: 2148 Cov.: 31 AF XY: 0.0408 AC XY: 29644 AN XY: 727032

African (AFR) AF: 0.0221 AC: 741 AN: 33470

American (AMR) AF: 0.112 AC: 4994 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0264 AC: 691 AN: 26132

East Asian (EAS) AF: 0.195 AC: 7749 AN: 39688

South Asian (SAS) AF: 0.0756 AC: 6517 AN: 86234

European-Finnish (FIN) AF: 0.0410 AC: 2187 AN: 53296

Middle Eastern (MID) AF: 0.0231 AC: 133 AN: 5768

European-Non Finnish (NFE) AF: 0.0295 AC: 32794 AN: 1111590

Other (OTH) AF: 0.0491 AC: 2962 AN: 60380

GnomAD4 genome AF: 0.0398 AC: 6065 AN: 152270 Hom.: 261 Cov.: 32 AF XY: 0.0425 AC XY: 3162 AN XY: 74454

African (AFR) AF: 0.0212 AC: 879 AN: 41560

American (AMR) AF: 0.0775 AC: 1186 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3470

East Asian (EAS) AF: 0.203 AC: 1046 AN: 5164

South Asian (SAS) AF: 0.0805 AC: 388 AN: 4822

European-Finnish (FIN) AF: 0.0383 AC: 407 AN: 10614

Middle Eastern (MID) AF: 0.0340 AC: 10 AN: 294

European-Non Finnish (NFE) AF: 0.0292 AC: 1983 AN: 68022

Other (OTH) AF: 0.0374 AC: 79 AN: 2114

Alfa AF: 0.0343 Hom.: 490

Bravo AF: 0.0416

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.0236 AC: 104

ESP6500EA AF: 0.0294 AC: 253

ExAC AF: 0.0574 AC: 6971

Asia WGS AF: 0.117 AC: 408 AN: 3478

EpiCase AF: 0.0305

EpiControl AF: 0.0288

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2015

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Tay-Sachs disease, variant AB Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

not provided Benign:2

Dec 15, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jun 09, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	9.4
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.057	N
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.0011	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.69	N
PhyloP100		-0.10
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.95	N
REVEL	Benign	0.041
Sift	Benign	0.22	T
Sift4G	Benign	0.57	T
Polyphen		0.017	B
Vest4		0.038
MPC		0.066
ClinPred		0.0076	T
GERP RS		0.34
PromoterAI		-0.031	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.41
Mutation Taster		=97/3	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: rs1048719; hg19: chr5-150632832; COSMIC: COSV64095521;