5-151253115-A-G

Variant summary

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

The ENST00000523466.5(GM2A):c.127-6640A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.358 in 882,268 control chromosomes in the GnomAD database, including 58,458 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10624 hom., cov: 32)
  • Exomes 𝑓: 0.36 (47834 hom.)
• Consequence: GM2A ENST00000523466.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.249

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 5-151253115-A-G is Benign according to our data. Variant chr5-151253115-A-G is described in ClinVar as [Benign]. Clinvar id is 352249.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.455 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GM2A	ENST00000523466.5	c.127-6640A>G		intron_variant		3

Frequencies

GnomAD3 genomes AF: 0.368 AC: 55897 AN: 151916 Hom.: 10596 Cov.: 32

Gnomad AFR AF: 0.408

Gnomad AMI AF: 0.314

Gnomad AMR AF: 0.454

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.363

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.384

GnomAD4 exome AF: 0.356 AC: 260035 AN: 730234 Hom.: 47834 Cov.: 10 AF XY: 0.354 AC XY: 137973 AN XY: 389626

Gnomad4 AFR exome AF: 0.411

Gnomad4 AMR exome AF: 0.518

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.508

Gnomad4 SAS exome AF: 0.358

Gnomad4 FIN exome AF: 0.310

Gnomad4 NFE exome AF: 0.327

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.368 AC: 55985 AN: 152034 Hom.: 10624 Cov.: 32 AF XY: 0.371 AC XY: 27573 AN XY: 74308

Gnomad4 AFR AF: 0.408

Gnomad4 AMR AF: 0.455

Gnomad4 ASJ AF: 0.448

Gnomad4 EAS AF: 0.471

Gnomad4 SAS AF: 0.364

Gnomad4 FIN AF: 0.304

Gnomad4 NFE AF: 0.323

Gnomad4 OTH AF: 0.388

Alfa AF: 0.343 Hom.: 3332

Bravo AF: 0.385

Asia WGS AF: 0.394 AC: 1368 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease, variant AB Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	7.7
Dann	Benign	0.46

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: rs2277028; hg19: chr5-150632676;