15-72350584-G-A

Variant names:

• chr15-72350584-G-A
• rs121907970
• NM_000520.6:c.739C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1 PP3 BP4 BP6_Very_Strong BS2

The NM_000520.6(HEXA):​c.739C>T​(p.Arg247Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00278 in 1,614,084 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R247Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (7 hom.)
• Consequence: HEXA NM_000520.6 missense
• Clinical Significance: Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1 B:6 O:3
• Conservation: PhyloP100: 0.906
• Publications: 28 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: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen

ENSG00000261460 (HGNC:58304):

ENSG00000260729 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 7 uncertain in NM_000520.6
• PP3: Multiple lines of computational evidence support a deleterious effect 8: BayesDel_addAF, BayesDel_noAF, Dann, Eigen, MutationAssessor, PROVEAN, REVEL, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster, phyloP100way_vertebrate was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.38934928).
• BP6: Variant 15-72350584-G-A is Benign according to our data. Variant chr15-72350584-G-A is described in ClinVar as Benign/Likely_benign|other. ClinVar VariationId is 3922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	NM_000520.6	MANE Select	c.739C>T	p.Arg247Trp	missense	Exon 7 of 14	NP_000511.2
	HEXA	NM_001318825.2		c.772C>T	p.Arg258Trp	missense	Exon 7 of 14	NP_001305754.1
	HEXA	NR_134869.3		n.781C>T		non_coding_transcript_exon	Exon 7 of 11

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEXA	ENST00000268097.10	TSL:1 MANE Select	c.739C>T	p.Arg247Trp	missense	Exon 7 of 14	ENSP00000268097.6
	HEXA	ENST00000567159.5	TSL:1	c.739C>T	p.Arg247Trp	missense	Exon 7 of 13	ENSP00000456489.1
	ENSG00000261460	ENST00000570175.1	TSL:1	n.1938G>A		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 270 AN: 152190 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00345

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00154 AC: 387 AN: 251482 AF XY: 0.00163

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000462

Gnomad NFE exome AF: 0.00315

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00289 AC: 4220 AN: 1461776 Hom.: 7 Cov.: 31 AF XY: 0.00283 AC XY: 2057 AN XY: 727196

African (AFR) AF: 0.000627 AC: 21 AN: 33478

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.000524 AC: 28 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00364 AC: 4049 AN: 1111942

Other (OTH) AF: 0.00172 AC: 104 AN: 60386

GnomAD4 genome AF: 0.00177 AC: 270 AN: 152308 Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115 AN XY: 74482

African (AFR) AF: 0.000722 AC: 30 AN: 41554

American (AMR) AF: 0.000131 AC: 2 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00345 AC: 235 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00277 Hom.: 1

Bravo AF: 0.00175

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00407 AC: 35

ExAC AF: 0.00164 AC: 199

EpiCase AF: 0.00327

EpiControl AF: 0.00213

ClinVar

Significance: Benign/Likely benign; other

Submissions summary: Pathogenic:1 Benign:6 Other:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3 Other:1

Aug 26, 2022

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 04, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31692161, 29482223, 26990548, 19858779, 22975760, 1384323, 17259242, 9169471)

Jan 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

HEXA: PP3, BS2

Apr 01, 2016

Eurofins Ntd Llc (ga)

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).

not specified Benign:2

May 08, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: HEXA c.739C>T (p.Arg247Trp) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0015 in 251482 control chromosomes in the gnomAD database, including 1 homozygote. The observed variant frequency is slightly higher than the estimated maximal expected allele frequency for a pathogenic variant in HEXA causing Tay-Sachs Disease phenotype (0.0014). c.739C>T is widely accepted in the field as a benign pseudodeficiency allele, with reduced HEXA enzymatic activity toward synthetic substrate(s), but not with the natural substrate. About 35% of non-Jewish individuals identified as heterozygotes by HEXA enzyme-based testing are carriers of a pseudodeficiency allele, while about 2% of Jewish individuals identified as heterozygotes by HEXA enzyme-based testing in carrier screening programs are actually heterozygous for the variant of interest (e.g. Triggs-Raine_1992). c.739C>T has been reported in the literature in individuals affected with Tay-Sachs Disease, however these reports do not provide unequivocal conclusions about association of the variant with Tay-Sachs Disease. At least one publication reports experimental evidence evaluating an impact on protein function and showed no damaging effect of this variant (e.g. Cao_1997). The following publications have been ascertained in the context of this evaluation (PMID: 9169471, 1384323). ClinVar contains an entry for this variant (Variation ID: 3922). Based on the evidence outlined above, the variant was classified as benign.

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Tay-Sachs disease Other:2

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Benign (Pseudodeficiency Allele) and reported on 04-03-2023 by Invitae. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

May 08, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: other

Review Status: criteria provided, single submitter

Collection Method: clinical testing

pseudodeficiency allele

BETA-HEXOSAMINIDASE A, PSEUDODEFICIENCY OF Pathogenic:1

Aug 01, 1993

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Hereditary ataxia Benign:1

Mar 04, 2020

Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Pathogenic	0.50
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.97	D
Eigen	Pathogenic	0.71
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.39	T
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.0	H
PhyloP100		0.91
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-7.8	D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MVP		1.0
MPC		0.76
ClinPred		0.30	T
GERP RS		3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.97
gMVP		0.91
Mutation Taster		=14/86	disease causing

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

Other links and lift over

dbSNP: rs121907970; hg19: chr15-72642925;