15-72344809-C-T

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_000520.6(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 NM_000520.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0200

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

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 35 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1526+637G>A		intron_variant	Intron 13 of 13	ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1559+637G>A		intron_variant	Intron 13 of 13		NP_001305754.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1526+637G>A		intron_variant	Intron 13 of 13	1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.608+637G>A		intron_variant	Intron 5 of 15	2		ENSP00000478716.1

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

Gnomad4 AFR AF: 0.00924

Gnomad4 AMR AF: 0.0132

Gnomad4 ASJ AF: 0.00893

Gnomad4 EAS AF: 0.0552

Gnomad4 SAS AF: 0.0126

Gnomad4 FIN AF: 0.0121

Gnomad4 NFE AF: 0.0150

Gnomad4 OTH AF: 0.0199

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.8
DANN	Benign	0.67

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: rs12904378; hg19: chr15-72637150;