chr15-72350584-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
Consequence
NM_000520.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -13 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.739C>T | p.Arg247Trp | missense_variant | Exon 7 of 14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.772C>T | p.Arg258Trp | missense_variant | Exon 7 of 14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.781C>T | non_coding_transcript_exon_variant | Exon 7 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.739C>T | p.Arg247Trp | missense_variant | Exon 7 of 14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.413-4259C>T | intron_variant | Intron 3 of 15 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes AF: 0.00177 AC: 270AN: 152190Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.00154 AC: 387AN: 251482Hom.: 1 AF XY: 0.00163 AC XY: 221AN XY: 135920
GnomAD4 exome AF: 0.00289 AC: 4220AN: 1461776Hom.: 7 Cov.: 31 AF XY: 0.00283 AC XY: 2057AN XY: 727196
GnomAD4 genome AF: 0.00177 AC: 270AN: 152308Hom.: 0 Cov.: 32 AF XY: 0.00154 AC XY: 115AN XY: 74482
ClinVar
Submissions by phenotype
not provided Benign:3Other:1
- Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles).
This variant is associated with the following publications: (PMID: 31692161, 29482223, 26990548, 19858779, 22975760, 1384323, 17259242, 9169471) -
HEXA: PP3, BS2 -
- -
not specified Benign:2
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. -
- -
Beta-hexosaminidase a, pseudodeficiency of Pathogenic:1
- -
Tay-Sachs disease Other:1
- pseudodeficiency allele
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at