rs2303448

Positions:

• chr15-72346371-C-T

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.1331-46G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0604 in 1,552,948 control chromosomes in the GnomAD database, including 3,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (224 hom., cov: 32)
  • Exomes 𝑓: 0.062 (3025 hom.)
• Consequence: HEXA NM_000520.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.50

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]

ENSG00000261460 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 15-72346371-C-T is Benign according to our data. Variant chr15-72346371-C-T is described in ClinVar as [Benign]. Clinvar id is 256350.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HEXA	NM_000520.6	c.1331-46G>A		intron_variant		ENST00000268097.10	NP_000511.2
HEXA	NM_001318825.2	c.1364-46G>A		intron_variant			NP_001305754.1
HEXA	NR_134869.3	n.1116-46G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HEXA	ENST00000268097.10	c.1331-46G>A		intron_variant		1	NM_000520.6	ENSP00000268097.6
ENSG00000260729	ENST00000379915.4	n.413-46G>A		intron_variant		2		ENSP00000478716.1

Frequencies

GnomAD3 genomes AF: 0.0457 AC: 6951 AN: 152120 Hom.: 225 Cov.: 32

Gnomad AFR AF: 0.0111

Gnomad AMI AF: 0.174

Gnomad AMR AF: 0.0287

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.0631

Gnomad FIN AF: 0.0433

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0639

Gnomad OTH AF: 0.0416

GnomAD3 exomes AF: 0.0552 AC: 13624 AN: 246764 Hom.: 452 AF XY: 0.0575 AC XY: 7674 AN XY: 133532

Gnomad AFR exome AF: 0.0115

Gnomad AMR exome AF: 0.0292

Gnomad ASJ exome AF: 0.0172

Gnomad EAS exome AF: 0.111

Gnomad SAS exome AF: 0.0664

Gnomad FIN exome AF: 0.0433

Gnomad NFE exome AF: 0.0634

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0619 AC: 86774 AN: 1400710 Hom.: 3025 Cov.: 22 AF XY: 0.0627 AC XY: 43934 AN XY: 700494

Gnomad4 AFR exome AF: 0.00918

Gnomad4 AMR exome AF: 0.0292

Gnomad4 ASJ exome AF: 0.0167

Gnomad4 EAS exome AF: 0.145

Gnomad4 SAS exome AF: 0.0664

Gnomad4 FIN exome AF: 0.0435

Gnomad4 NFE exome AF: 0.0640

Gnomad4 OTH exome AF: 0.0534

GnomAD4 genome AF: 0.0456 AC: 6947 AN: 152238 Hom.: 224 Cov.: 32 AF XY: 0.0447 AC XY: 3325 AN XY: 74430

Gnomad4 AFR AF: 0.0111

Gnomad4 AMR AF: 0.0286

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.0630

Gnomad4 FIN AF: 0.0433

Gnomad4 NFE AF: 0.0640

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0571 Hom.: 148

Bravo AF: 0.0428

Asia WGS AF: 0.0710 AC: 247 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Tay-Sachs disease Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 31, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.72
DANN	Benign	0.61

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: rs2303448; hg19: chr15-72638712;