chr5-151253271-G-A

Position:

chr5-151253271-G-A

Variant summary

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

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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A19A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.040 ( 261 hom., cov: 32)

Exomes 𝑓: 0.040 ( 2148 hom. )

Consequence

GM2A
NM_000405.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.100

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=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 id 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/exons	MANE	UniProt
GM2A	NM_000405.5 linkuse as main transcript	c.55G>A	p.Ala19Thr	missense_variant	1/4	ENST00000357164.4
GM2A	NM_001167607.3 linkuse as main transcript	c.55G>A	p.Ala19Thr	missense_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GM2A	ENST00000357164.4 linkuse as main transcript	c.55G>A	p.Ala19Thr	missense_variant	1/4	1	NM_000405.5	P1
GM2A	ENST00000523466.5 linkuse as main transcript	c.127-6484G>A		intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0399

AC:

6070

AN:

152152

Hom.:

263

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0607

AC:

15228

AN:

251070

Hom.:

810

AF XY:

0.0591

AC XY:

8029

AN XY:

135744

show subpopulations

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 SAS exome

AF:

0.0767

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.:

AF XY:

0.0408

AC XY:

29644

AN XY:

727032

show subpopulations

Gnomad4 AFR exome

AF:

0.0221

Gnomad4 AMR exome

AF:

0.112

Gnomad4 ASJ exome

AF:

0.0264

Gnomad4 EAS exome

AF:

0.195

Gnomad4 SAS exome

AF:

0.0756

Gnomad4 FIN exome

AF:

0.0410

Gnomad4 NFE exome

AF:

0.0295

Gnomad4 OTH exome

AF:

0.0491

GnomAD4 genome

AF:

0.0398

AC:

6065

AN:

152270

Hom.:

261

Cov.:

AF XY:

0.0425

AC XY:

3162

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.0212

Gnomad4 AMR

AF:

0.0775

Gnomad4 ASJ

AF:

0.0231

Gnomad4 EAS

AF:

0.203

Gnomad4 SAS

AF:

0.0805

Gnomad4 FIN

AF:

0.0383

Gnomad4 NFE

AF:

0.0292

Gnomad4 OTH

AF:

0.0374

Alfa

AF:

0.0331

Hom.:

323

Bravo

AF:

0.0416

TwinsUK

AF:

0.0243

AC:

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

LINK: link

Submissions by phenotype

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)	Nov 03, 2015	- -

Tay-Sachs disease, variant AB

Benign:2

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 provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 09, 2021	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.4

DANN

Benign

0.96

DEOGEN2

Benign

0.13

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.057

LIST_S2

Benign

0.52

MetaRNN

Benign

0.0011

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.95

REVEL

Benign

0.041

Sift

Benign

0.22

Sift4G

Benign

0.57

Polyphen

0.017

Vest4

0.038

MPC

0.066

ClinPred

0.0076

GERP RS

0.34

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.076

gMVP

0.41

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