rs76075374

chr15-72343502-C-T

Variant summary

Our verdict is Benign. Variant got -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, single submitter U:1
• 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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd at 22 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HEXA	NM_000520.6	c.*575G>A		3_prime_UTR_variant	14/14	ENST00000268097.10
HEXA	NM_001318825.2	c.*575G>A		3_prime_UTR_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HEXA	ENST00000268097.10	c.*575G>A		3_prime_UTR_variant	14/14	1	NM_000520.6	P1
	ENST00000570175.1	n.166-1884C>T		intron_variant, non_coding_transcript_variant		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

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00532

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0269

Gnomad4 OTH exome AF: 0.0303

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

Gnomad4 AMR AF: 0.00988

Gnomad4 ASJ AF: 0.0144

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00415

Gnomad4 FIN AF: 0.0125

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0138

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:1

Revision: criteria provided, single submitter

Submissions by phenotype

Tay-Sachs disease Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
Cadd	Benign	5.3
Dann	Benign	0.78

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;