15-72343502-C-T

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

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]

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 FAILED 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	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

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 8

Gnomad4 AMR exome AF: 0.0127 AC: 5 AN: 394

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 2

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 16

Gnomad4 SAS exome AF: 0.00532 AC: 1 AN: 188

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 4

Gnomad4 NFE exome AF: 0.0269 AC: 31 AN: 1154

Gnomad4 Remaining exome 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

Gnomad4 AFR AF: 0.00436 AC: 0.00435788 AN: 0.00435788

Gnomad4 AMR AF: 0.00988 AC: 0.00987961 AN: 0.00987961

Gnomad4 ASJ AF: 0.0144 AC: 0.0144009 AN: 0.0144009

Gnomad4 EAS AF: 0.000193 AC: 0.000193199 AN: 0.000193199

Gnomad4 SAS AF: 0.00415 AC: 0.0041511 AN: 0.0041511

Gnomad4 FIN AF: 0.0125 AC: 0.0124552 AN: 0.0124552

Gnomad4 NFE AF: 0.0219 AC: 0.0218702 AN: 0.0218702

Gnomad4 OTH AF: 0.0138 AC: 0.0137833 AN: 0.0137833

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
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

Publications

LitVar

Other links and lift over

dbSNP: rs76075374; hg19: chr15-72635843;