rs153477

Variant names:

• chr5-151259848-A-G
• rs153477
• NM_000405.5:c.175A>G

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.175A>G​(p.Ile59Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.634 in 1,609,530 control chromosomes in the GnomAD database, including 326,470 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 (★★). Synonymous variant affecting the same amino acid position (i.e. I59I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.63 (30424 hom., cov: 33)
  • Exomes 𝑓: 0.63 (296046 hom.)
• Consequence: GM2A NM_000405.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.864
• Publications: 42 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, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.319748E-6).
• BP6: Variant 5-151259848-A-G is Benign according to our data. Variant chr5-151259848-A-G is described in ClinVar as Benign. ClinVar VariationId is 167150.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.74 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.175A>G	p.Ile59Val	missense	Exon 2 of 4	NP_000396.2
	GM2A	NM_001167607.3		c.175A>G	p.Ile59Val	missense	Exon 2 of 4	NP_001161079.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GM2A	ENST00000357164.4	TSL:1 MANE Select	c.175A>G	p.Ile59Val	missense	Exon 2 of 4	ENSP00000349687.3	P17900
	GM2A	ENST00000523004.1	TSL:1	c.49A>G	p.Ile17Val	missense	Exon 1 of 2	ENSP00000430541.1	H0YBY3
	GM2A	ENST00000523466.5	TSL:3	c.220A>G	p.Ile74Val	missense	Exon 3 of 4	ENSP00000429100.1	E5RJD0

Frequencies

GnomAD3 genomes AF: 0.629 AC: 95647 AN: 151956 Hom.: 30398 Cov.: 33

Gnomad AFR AF: 0.585

Gnomad AMI AF: 0.738

Gnomad AMR AF: 0.695

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.648

Gnomad SAS AF: 0.761

Gnomad FIN AF: 0.614

Gnomad MID AF: 0.756

Gnomad NFE AF: 0.628

Gnomad OTH AF: 0.657

GnomAD2 exomes AF: 0.667 AC: 167416 AN: 251014 AF XY: 0.670

Gnomad AFR exome AF: 0.581

Gnomad AMR exome AF: 0.777

Gnomad ASJ exome AF: 0.696

Gnomad EAS exome AF: 0.640

Gnomad FIN exome AF: 0.621

Gnomad NFE exome AF: 0.629

Gnomad OTH exome AF: 0.673

GnomAD4 exome AF: 0.635 AC: 925008 AN: 1457456 Hom.: 296046 Cov.: 36 AF XY: 0.639 AC XY: 463362 AN XY: 725224

African (AFR) AF: 0.592 AC: 19787 AN: 33398

American (AMR) AF: 0.773 AC: 34534 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.690 AC: 18015 AN: 26102

East Asian (EAS) AF: 0.659 AC: 26136 AN: 39690

South Asian (SAS) AF: 0.768 AC: 66216 AN: 86176

European-Finnish (FIN) AF: 0.618 AC: 33027 AN: 53408

Middle Eastern (MID) AF: 0.754 AC: 4341 AN: 5760

European-Non Finnish (NFE) AF: 0.617 AC: 683942 AN: 1108008

Other (OTH) AF: 0.648 AC: 39010 AN: 60226

GnomAD4 genome AF: 0.629 AC: 95729 AN: 152074 Hom.: 30424 Cov.: 33 AF XY: 0.631 AC XY: 46943 AN XY: 74336

African (AFR) AF: 0.585 AC: 24284 AN: 41476

American (AMR) AF: 0.696 AC: 10639 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2358 AN: 3470

East Asian (EAS) AF: 0.648 AC: 3346 AN: 5166

South Asian (SAS) AF: 0.761 AC: 3667 AN: 4820

European-Finnish (FIN) AF: 0.614 AC: 6480 AN: 10560

Middle Eastern (MID) AF: 0.752 AC: 221 AN: 294

European-Non Finnish (NFE) AF: 0.628 AC: 42679 AN: 67988

Other (OTH) AF: 0.657 AC: 1382 AN: 2104

Alfa AF: 0.633 Hom.: 92211

Bravo AF: 0.636

TwinsUK AF: 0.608 AC: 2253

ALSPAC AF: 0.612 AC: 2359

ESP6500AA AF: 0.574 AC: 2528

ESP6500EA AF: 0.627 AC: 5388

ExAC AF: 0.665 AC: 80704

Asia WGS AF: 0.707 AC: 2460 AN: 3478

EpiCase AF: 0.629

EpiControl AF: 0.640

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Tay-Sachs disease, variant AB (3)
-	-	2	not specified (2)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.075
DANN	Benign	0.28
DEOGEN2	Benign	0.084	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.0047	N
LIST_S2	Benign	0.032	T
MetaRNN	Benign	0.0000013	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-1.9	N
PhyloP100		-0.86
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.62	N
REVEL	Benign	0.13
Sift	Benign	0.42	T
Sift4G	Benign	0.48	T
Polyphen		0.0	B
Vest4		0.010
MPC		0.058
ClinPred		0.0040	T
GERP RS		-0.55
PromoterAI		0.014	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.072
gMVP		0.44
Mutation Taster		=98/2	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: rs153477; hg19: chr5-150639409; COSMIC: COSV64095541;