15-72347356-C-G

Position:

• chr15-72347356-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000520.6(HEXA):​c.1146+330G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.126 in 150,826 control chromosomes in the GnomAD database, including 1,792 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.13 (1792 hom., cov: 31)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.959

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.02).
• BP6: Variant 15-72347356-C-G is Benign according to our data. Variant chr15-72347356-C-G is described in ClinVar as [Benign]. Clinvar id is 1225006.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1146+330G>C		intron_variant		ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1179+330G>C		intron_variant			NP_001305754.1
HEXA	NR_134869.3	n.1115+692G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1146+330G>C		intron_variant		1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-1031G>C		intron_variant		2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.126 AC: 19014 AN: 150706 Hom.: 1778 Cov.: 31

Gnomad AFR AF: 0.253

Gnomad AMI AF: 0.135

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0249

Gnomad EAS AF: 0.200

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.0522

Gnomad MID AF: 0.0516

Gnomad NFE AF: 0.0663

Gnomad OTH AF: 0.121

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

GnomAD4 genome AF: 0.126 AC: 19074 AN: 150826 Hom.: 1792 Cov.: 31 AF XY: 0.124 AC XY: 9095 AN XY: 73548

Gnomad4 AFR AF: 0.254

Gnomad4 AMR AF: 0.117

Gnomad4 ASJ AF: 0.0249

Gnomad4 EAS AF: 0.200

Gnomad4 SAS AF: 0.0701

Gnomad4 FIN AF: 0.0522

Gnomad4 NFE AF: 0.0663

Gnomad4 OTH AF: 0.127

Alfa AF: 0.0368 Hom.: 32

Bravo AF: 0.136

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Dec 31, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.31
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs12910617; hg19: chr15-72639697;