rs76075374

Variant names:

• chr15-72343502-C-T
• rs76075374
• NM_000520.6:c.*575G>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000520.6(HEXA):​c.*575G>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 0.0137 in 154,014 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (22 hom., cov: 33)
  • Exomes 𝑓: 0.021 (1 hom.)
• Consequence: HEXA NM_000520.6 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.147
• Publications: 3 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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2067/152182) while in subpopulation NFE AF = 0.0219 (1487/67992). AF 95% confidence interval is 0.0209. There are 22 homozygotes in GnomAd4. There are 1008 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.*575G>A		3_prime_UTR_variant	Exon 14 of 14	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.*575G>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.*575G>A		3_prime_UTR_variant	Exon 14 of 14	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.608+1944G>A		intron_variant	Intron 5 of 15	2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0136 AC: 2068 AN: 152064 Hom.: 22 Cov.: 33

Gnomad AFR AF: 0.00437

Gnomad AMI AF: 0.0110

Gnomad AMR AF: 0.00996

Gnomad ASJ AF: 0.0144

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00415

Gnomad FIN AF: 0.0125

Gnomad MID AF: 0.0191

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0139

GnomAD4 exome AF: 0.0213 AC: 39 AN: 1832 Hom.: 1 Cov.: 0 AF XY: 0.0154 AC XY: 15 AN XY: 974

African (AFR) AF: 0.00 AC: 0 AN: 8

American (AMR) AF: 0.0127 AC: 5 AN: 394

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AF: 0.00 AC: 0 AN: 16

South Asian (SAS) AF: 0.00532 AC: 1 AN: 188

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0269 AC: 31 AN: 1154

Other (OTH) AF: 0.0303 AC: 2 AN: 66

GnomAD4 genome AF: 0.0136 AC: 2067 AN: 152182 Hom.: 22 Cov.: 33 AF XY: 0.0135 AC XY: 1008 AN XY: 74414

African (AFR) AF: 0.00436 AC: 181 AN: 41534

American (AMR) AF: 0.00988 AC: 151 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0144 AC: 50 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00415 AC: 20 AN: 4818

European-Finnish (FIN) AF: 0.0125 AC: 132 AN: 10598

Middle Eastern (MID) AF: 0.0205 AC: 6 AN: 292

European-Non Finnish (NFE) AF: 0.0219 AC: 1487 AN: 67992

Other (OTH) AF: 0.0138 AC: 29 AN: 2104

Alfa AF: 0.0192 Hom.: 9

Bravo AF: 0.0137

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	5.3
DANN	Benign	0.78
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism

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: rs76075374; hg19: chr15-72635843;