rs73440586

Positions:

• chr15-72349307-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000520.6(HEXA):​c.806-48G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0153 in 1,417,158 control chromosomes in the GnomAD database, including 1,471 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (690 hom., cov: 32)
  • Exomes 𝑓: 0.010 (781 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.142

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:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 15-72349307-C-A is Benign according to our data. Variant chr15-72349307-C-A is described in ClinVar as [Benign]. Clinvar id is 256353.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.17 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.806-48G>T		intron_variant		ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.839-48G>T		intron_variant			NP_001305754.1
HEXA	NR_134869.3	n.848-48G>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.806-48G>T		intron_variant		1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-2982G>T		intron_variant		2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0563 AC: 8572 AN: 152148 Hom.: 685 Cov.: 32

Gnomad AFR AF: 0.174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0706

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.00311

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00955

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.0492

GnomAD3 exomes AF: 0.0268 AC: 6640 AN: 247350 Hom.: 441 AF XY: 0.0204 AC XY: 2735 AN XY: 134238

Gnomad AFR exome AF: 0.177

Gnomad AMR exome AF: 0.0965

Gnomad ASJ exome AF: 0.00151

Gnomad EAS exome AF: 0.000873

Gnomad SAS exome AF: 0.00256

Gnomad FIN exome AF: 0.000282

Gnomad NFE exome AF: 0.00242

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0103 AC: 13022 AN: 1264892 Hom.: 781 Cov.: 18 AF XY: 0.00906 AC XY: 5798 AN XY: 639894

Gnomad4 AFR exome AF: 0.181

Gnomad4 AMR exome AF: 0.0938

Gnomad4 ASJ exome AF: 0.00156

Gnomad4 EAS exome AF: 0.000464

Gnomad4 SAS exome AF: 0.00317

Gnomad4 FIN exome AF: 0.000228

Gnomad4 NFE exome AF: 0.00237

Gnomad4 OTH exome AF: 0.0170

GnomAD4 genome AF: 0.0565 AC: 8607 AN: 152266 Hom.: 690 Cov.: 32 AF XY: 0.0555 AC XY: 4134 AN XY: 74450

Gnomad4 AFR AF: 0.174

Gnomad4 AMR AF: 0.0710

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.00311

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00253

Gnomad4 OTH AF: 0.0530

Alfa AF: 0.0212 Hom.: 46

Bravo AF: 0.0679

Asia WGS AF: 0.0240 AC: 83 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 20, 2019	- -

Tay-Sachs disease Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Apr 12, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	1.5
DANN	Benign	0.55

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: rs73440586; hg19: chr15-72641648;