rs3087652

Variant names:

• chr15-72343562-C-T
• rs3087652
• NM_000520.6:c.*515G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000520.6(HEXA):​c.*515G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.754 in 162,730 control chromosomes in the GnomAD database, including 52,573 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.74 (48315 hom., cov: 32)
  • Exomes 𝑓: 0.89 (4258 hom.)
• Consequence: HEXA NM_000520.6 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0290
• Publications: 8 publications found

Genes affected

HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]

HEXA Gene-Disease associations (from GenCC):

• Tay-Sachs disease

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000260729 (HGNC:):

ENSG00000261460 (HGNC:58304):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.935 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.*515G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.*515G>A		3_prime_UTR_variant	Exon 14 of 14		NP_001305754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.*515G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.608+1884G>A		intron_variant	Intron 5 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113253 AN: 151962 Hom.: 48331 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.867

Gnomad AMR AF: 0.844

Gnomad ASJ AF: 0.982

Gnomad EAS AF: 0.762

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.909

Gnomad MID AF: 0.924

Gnomad NFE AF: 0.941

Gnomad OTH AF: 0.788

GnomAD4 exome AF: 0.886 AC: 9436 AN: 10650 Hom.: 4258 Cov.: 0 AF XY: 0.891 AC XY: 5036 AN XY: 5654

African (AFR) AF: 0.193 AC: 37 AN: 192

American (AMR) AF: 0.847 AC: 2047 AN: 2416

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 64 AN: 66

East Asian (EAS) AF: 0.727 AC: 490 AN: 674

South Asian (SAS) AF: 0.934 AC: 1520 AN: 1628

European-Finnish (FIN) AF: 0.929 AC: 78 AN: 84

Middle Eastern (MID) AF: 0.850 AC: 17 AN: 20

European-Non Finnish (NFE) AF: 0.933 AC: 4830 AN: 5178

Other (OTH) AF: 0.901 AC: 353 AN: 392

GnomAD4 genome AF: 0.745 AC: 113244 AN: 152080 Hom.: 48315 Cov.: 32 AF XY: 0.750 AC XY: 55730 AN XY: 74348

African (AFR) AF: 0.294 AC: 12168 AN: 41454

American (AMR) AF: 0.843 AC: 12892 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.982 AC: 3411 AN: 3472

East Asian (EAS) AF: 0.762 AC: 3927 AN: 5156

South Asian (SAS) AF: 0.934 AC: 4494 AN: 4812

European-Finnish (FIN) AF: 0.909 AC: 9624 AN: 10588

Middle Eastern (MID) AF: 0.922 AC: 271 AN: 294

European-Non Finnish (NFE) AF: 0.941 AC: 64020 AN: 68006

Other (OTH) AF: 0.783 AC: 1650 AN: 2106

Alfa AF: 0.801 Hom.: 6916

Bravo AF: 0.719

Asia WGS AF: 0.795 AC: 2765 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	3.2
DANN	Benign	0.41
PhyloP100		0.029
Mutation Taster		=100/0	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: rs3087652; hg19: chr15-72635903;