15-72350584-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4BP6_Very_StrongBS2

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 (★★).

Frequency

Genomes: 𝑓 0.0018 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0029 ( 7 hom. )

Consequence

HEXA
NM_000520.6 missense

Scores

12
4
3

Clinical Significance

Benign/Likely benign; other criteria provided, multiple submitters, no conflicts P:1B:5O:2

Conservation

PhyloP100: 0.906
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

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 [Likely_benign, other]. Clinvar id is 3922.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-72350584-G-A is described in Lovd as [Likely_benign]. Variant chr15-72350584-G-A is described in Lovd as [Pathogenic].
BS2
High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HEXANM_000520.6 linkc.739C>T p.Arg247Trp missense_variant Exon 7 of 14 ENST00000268097.10 NP_000511.2 P06865-1A0A0S2Z3W3
HEXANM_001318825.2 linkc.772C>T p.Arg258Trp missense_variant Exon 7 of 14 NP_001305754.1 P06865H3BP20B4DVA7
HEXANR_134869.3 linkn.781C>T non_coding_transcript_exon_variant Exon 7 of 11

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HEXAENST00000268097.10 linkc.739C>T p.Arg247Trp missense_variant Exon 7 of 14 1 NM_000520.6 ENSP00000268097.6 P06865-1
ENSG00000260729ENST00000379915.4 linkn.413-4259C>T intron_variant Intron 3 of 15 2 ENSP00000478716.1 A0A087WUJ7

Frequencies

GnomAD3 genomes
AF:
0.00177
AC:
270
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
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
GnomAD3 exomes
AF:
0.00154
AC:
387
AN:
251482
Hom.:
1
AF XY:
0.00163
AC XY:
221
AN XY:
135920
show subpopulations
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 SAS exome
AF:
0.00
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
show subpopulations
Gnomad4 AFR exome
AF:
0.000627
Gnomad4 AMR exome
AF:
0.000179
Gnomad4 ASJ exome
AF:
0.000191
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000464
Gnomad4 FIN exome
AF:
0.000524
Gnomad4 NFE exome
AF:
0.00364
Gnomad4 OTH exome
AF:
0.00172
GnomAD4 genome
AF:
0.00177
AC:
270
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.00154
AC XY:
115
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.000722
Gnomad4 AMR
AF:
0.000131
Gnomad4 ASJ
AF:
0.000288
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.00345
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.00280
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:1Benign:5Other:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3Other:1
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).

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 -

Aug 26, 2022
Quest Diagnostics Nichols Institute San Juan Capistrano
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Beta-hexosaminidase a, pseudodeficiency of Pathogenic:1
Aug 01, 1993
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

Tay-Sachs disease Other:1
May 08, 2017
Labcorp Genetics (formerly Invitae), Labcorp
Significance: other
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- pseudodeficiency allele

Computational scores

Source: dbNSFP v4.3

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;.;D
Eigen
Pathogenic
0.71
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
1.0
D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Benign
0.39
T;T;T
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Pathogenic
4.0
H;.;.
PrimateAI
Uncertain
0.70
T
PROVEAN
Pathogenic
-7.8
D;D;D
REVEL
Pathogenic
0.93
Sift
Pathogenic
0.0
D;D;D
Sift4G
Pathogenic
0.0
D;D;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

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs121907970; hg19: chr15-72642925; API