15-72344809-C-T

Variant names:

• chr15-72344809-C-T
• rs12904378
• NM_000520.6:c.1526+637G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The ENST00000268097.10(HEXA):​c.1526+637G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 152,270 control chromosomes in the GnomAD database, including 35 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 0.014 (35 hom., cov: 32)
• Consequence: HEXA ENST00000268097.10 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0142 (2166/152270) while in subpopulation EAS AF = 0.0552 (286/5184). AF 95% confidence interval is 0.0499. There are 35 homozygotes in GnomAd4. There are 1037 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000268097.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.1526+637G>A		intron	N/A	NP_000511.2
	HEXA	NM_001318825.2		c.1559+637G>A		intron	N/A	NP_001305754.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1526+637G>A		intron	N/A	ENSP00000268097.6
	ENSG00000260729	ENST00000379915.4	TSL:2	n.608+637G>A		intron	N/A	ENSP00000478716.1
	ENSG00000261460	ENST00000570175.1	TSL:1	n.166-577C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0142 AC: 2159 AN: 152152 Hom.: 35 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0132

Gnomad ASJ AF: 0.00893

Gnomad EAS AF: 0.0554

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0150

Gnomad OTH AF: 0.0172

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0142 AC: 2166 AN: 152270 Hom.: 35 Cov.: 32 AF XY: 0.0139 AC XY: 1037 AN XY: 74428

African (AFR) AF: 0.00924 AC: 384 AN: 41548

American (AMR) AF: 0.0132 AC: 202 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00893 AC: 31 AN: 3470

East Asian (EAS) AF: 0.0552 AC: 286 AN: 5184

South Asian (SAS) AF: 0.0126 AC: 61 AN: 4824

European-Finnish (FIN) AF: 0.0121 AC: 128 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0150 AC: 1018 AN: 68026

Other (OTH) AF: 0.0199 AC: 42 AN: 2110

Alfa AF: 0.00745 Hom.: 4

Bravo AF: 0.0135

Asia WGS AF: 0.0530 AC: 182 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.67
PhyloP100		-0.020
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: rs12904378; hg19: chr15-72637150;