Genetic Variant GM2A:c.127-6621C>G (chr5-151253134-C-G) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000523466.5(GM2A):c.127-6621C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000115 in 869,694 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

GM2A
ENST00000523466.5 intron

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.448

Publications

0 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, Labcorp Genetics (formerly Invitae), ClinGen

GM2A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.77).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GM2A	NM_000405.5 link	c.-83C>G		upstream_gene_variant		ENST00000357164.4	NP_000396.2	P17900
GM2A	NM_001167607.3 link	c.-83C>G		upstream_gene_variant			NP_001161079.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GM2A	ENST00000523466.5 link	c.127-6621C>G		intron_variant	Intron 2 of 3	3		ENSP00000429100.1		E5RJD0
GM2A	ENST00000357164.4 link	c.-83C>G		upstream_gene_variant		1	NM_000405.5	ENSP00000349687.3		P17900

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000115

AC:

AN:

869694

Hom.:

Cov.:

AF XY:

0.00000219

AC XY:

AN XY:

456300

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22052

American (AMR)

AF:

0.00

AC:

AN:

43800

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22428

East Asian (EAS)

AF:

0.00

AC:

AN:

36906

South Asian (SAS)

AF:

0.00

AC:

AN:

74400

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51122

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3784

European-Non Finnish (NFE)

AF:

0.00000174

AC:

AN:

574234

Other (OTH)

AF:

0.00

AC:

AN:

40968

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Tay-Sachs disease, variant AB

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.77

CADD

Benign

(source)

DANN

Benign

0.68

PhyloP100

0.45

PromoterAI

-0.51

Under-expression

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over