rs9324685

chr5-151267479-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000405.5(GM2A):c.*28C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0496 in 1,613,684 control chromosomes in the GnomAD database, including 4,353 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.089 (1089 hom., cov: 32)
  • Exomes 𝑓: 0.046 (3264 hom.)
• Consequence: GM2A NM_000405.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-151267479-C-T is Benign according to our data. Variant chr5-151267479-C-T is described in ClinVar as [Benign]. Clinvar id is 256029.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.247 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GM2A	NM_000405.5	c.*28C>T		3_prime_UTR_variant	4/4	ENST00000357164.4
GM2A	NM_001167607.3	c.413-13C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GM2A	ENST00000357164.4	c.*28C>T		3_prime_UTR_variant	4/4	1	NM_000405.5	P1

Frequencies

GnomAD3 genomes AF: 0.0888 AC: 13508 AN: 152092 Hom.: 1086 Cov.: 32

Gnomad AFR AF: 0.193

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0683

Gnomad ASJ AF: 0.0276

Gnomad EAS AF: 0.259

Gnomad SAS AF: 0.0968

Gnomad FIN AF: 0.0398

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0699

GnomAD3 exomes AF: 0.0716 AC: 17956 AN: 250922 Hom.: 1252 AF XY: 0.0684 AC XY: 9279 AN XY: 135632

Gnomad AFR exome AF: 0.200

Gnomad AMR exome AF: 0.0705

Gnomad ASJ exome AF: 0.0289

Gnomad EAS exome AF: 0.258

Gnomad SAS exome AF: 0.0850

Gnomad FIN exome AF: 0.0441

Gnomad NFE exome AF: 0.0301

Gnomad OTH exome AF: 0.0473

GnomAD4 exome AF: 0.0455 AC: 66567 AN: 1461474 Hom.: 3264 Cov.: 34 AF XY: 0.0460 AC XY: 33477 AN XY: 727046

Gnomad4 AFR exome AF: 0.198

Gnomad4 AMR exome AF: 0.0692

Gnomad4 ASJ exome AF: 0.0289

Gnomad4 EAS exome AF: 0.250

Gnomad4 SAS exome AF: 0.0854

Gnomad4 FIN exome AF: 0.0439

Gnomad4 NFE exome AF: 0.0292

Gnomad4 OTH exome AF: 0.0630

GnomAD4 genome AF: 0.0889 AC: 13528 AN: 152210 Hom.: 1089 Cov.: 32 AF XY: 0.0908 AC XY: 6759 AN XY: 74412

Gnomad4 AFR AF: 0.193

Gnomad4 AMR AF: 0.0680

Gnomad4 ASJ AF: 0.0276

Gnomad4 EAS AF: 0.259

Gnomad4 SAS AF: 0.0967

Gnomad4 FIN AF: 0.0398

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0691

Alfa AF: 0.0511 Hom.: 155

Bravo AF: 0.0954

Asia WGS AF: 0.160 AC: 556 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Tay-Sachs disease, variant AB Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.9
Dann	Benign	0.44

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

Other links and lift over

dbSNP: rs9324685; hg19: chr5-150647040; COSMIC: COSV64095301; COSMIC: COSV64095301;