5-151253271-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 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

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.100

Publications

18 publications found

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 Gene-Disease associations (from GenCC):

Tay-Sachs disease AB variant
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

GM2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000405.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	NM_000405.5	MANE Select	c.55G>A	p.Ala19Thr	missense	Exon 1 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.55G>A	p.Ala19Thr	missense	Exon 1 of 4	NP_001161079.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GM2A	ENST00000357164.4	TSL:1 MANE Select	c.55G>A	p.Ala19Thr	missense	Exon 1 of 4	ENSP00000349687.3	P17900
GM2A	ENST00000937902.1		c.55G>A	p.Ala19Thr	missense	Exon 1 of 3	ENSP00000607961.1
GM2A	ENST00000523466.5	TSL:3	c.127-6484G>A		intron	N/A	ENSP00000429100.1	E5RJD0

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

GnomAD2 exomes

AF:

0.0607

AC:

15228

AN:

251070

AF XY:

0.0591

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 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

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

3088

6175

9263

12350

15438

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1432

2864

4296

5728

7160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0398

AC:

6065

AN:

152270

Hom.:

261

Cov.:

AF XY:

0.0425

AC XY:

3162

AN XY:

74454

show subpopulations

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:

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:

AN:

294

European-Non Finnish (NFE)

AF:

0.0292

AC:

1983

AN:

68022

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

277

554

830

1107

1384

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0343

Hom.:

490

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

not specified (2)

Tay-Sachs disease, variant AB (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.69

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.4

(source)

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

PhyloP100

-0.10

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

PromoterAI

-0.031

Neutral

(source)

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)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over