15-72347356-C-G

Variant names:

• chr15-72347356-C-G
• rs12910617
• NM_000520.6:c.1146+330G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 4 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Myriad Women's Health, ClinGen

ENSG00000260729 (HGNC:):

CELF6-AS1 (HGNC:58304):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000520.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.1146+330G>C		intron	N/A	NP_000511.2	P06865-1
	HEXA	NM_001318825.2		c.1179+330G>C		intron	N/A	NP_001305754.1	H3BP20
	HEXA	NR_134869.3		n.1115+692G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.1146+330G>C		intron	N/A	ENSP00000268097.6	P06865-1
	HEXA	ENST00000567159.5	TSL:1	c.1146+330G>C		intron	N/A	ENSP00000456489.1	H3BS10
	ENSG00000260729	ENST00000379915.4	TSL:2	n.413-1031G>C		intron	N/A	ENSP00000478716.1	A0A087WUJ7

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

African (AFR) AF: 0.254 AC: 10462 AN: 41250

American (AMR) AF: 0.117 AC: 1766 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.0249 AC: 86 AN: 3460

East Asian (EAS) AF: 0.200 AC: 1005 AN: 5022

South Asian (SAS) AF: 0.0701 AC: 329 AN: 4696

European-Finnish (FIN) AF: 0.0522 AC: 540 AN: 10346

Middle Eastern (MID) AF: 0.0521 AC: 15 AN: 288

European-Non Finnish (NFE) AF: 0.0663 AC: 4482 AN: 67642

Other (OTH) AF: 0.127 AC: 266 AN: 2098

Alfa AF: 0.0368 Hom.: 32

Bravo AF: 0.136

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.29
DANN	Benign	0.31
PhyloP100		-0.96
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs12910617;

hg19: chr15-72639697;