rs121907984
Variant summary
Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2
The NM_000521.4(HEXB):c.1627G>A(p.Ala543Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00048 in 1,612,544 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign,other (★★). Synonymous variant affecting the same amino acid position (i.e. A543A) has been classified as Likely benign.
Frequency
Consequence
NM_000521.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXB | NM_000521.4 | c.1627G>A | p.Ala543Thr | missense_variant | 14/14 | ENST00000261416.12 | |
HEXB | NM_001292004.2 | c.952G>A | p.Ala318Thr | missense_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.1627G>A | p.Ala543Thr | missense_variant | 14/14 | 1 | NM_000521.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000309 AC: 47AN: 152096Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000860 AC: 216AN: 251138Hom.: 3 AF XY: 0.00119 AC XY: 162AN XY: 135758
GnomAD4 exome AF: 0.000497 AC: 726AN: 1460328Hom.: 13 Cov.: 29 AF XY: 0.000666 AC XY: 484AN XY: 726546
GnomAD4 genome ? AF: 0.000315 AC: 48AN: 152216Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74426
ClinVar
Submissions by phenotype
Sandhoff disease Benign:5
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 18, 2018 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 21, 2024 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jan 01, 2019 | - - |
Benign, no assertion criteria provided | clinical testing | Natera, Inc. | Jan 09, 2020 | - - |
not provided Benign:1Other:1
other, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Dec 18, 2012 | - Variant classified as "other reportable" ??? variant is clinically benign (not associated with disease) but is reported when observed (e.g. pseudodeficiency alleles). |
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 31, 2016 | Variant summary: The HEXB c.1627G>A (p.Ala543Thr) variant causes a missense change involving a conserved nucleotide with 5/5 in silico tools predict a damaging outcome. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 115/120804 (1/1052, 1 homozygote), predominantly observed in the South Asian cohort, 92/16490 (1/179, 1 homozygote), which exceeds the estimated maximal expected allele frequency for a pathogenic HEXB variant of 1/676. Therefore, suggesting the variant is a common polymorphism found in population(s) of South Asian origin. The variant of interest has been reported in multiple affected and healthy homozygous individuals via publications. Functional studies have shown that the variant of interest is a heat labile allele, meaning that it leads to reduction in enzyme activity and mightresult in a false non-TSD or non-SD diagnosis. Likewise, a doubly heterozygous person, for TSD and for HLB, could be misdiagnosed as a normal homozygote. In addition, multiple reputable clinical diagnostic laboratories/databases cite the variant as "benign," along with the reporting cautionary awareness for the heat labile aspect. Therefore, to indicate the potential for the variant to cause false negative results, a classification of "Probable Normal Variant/Likely Benign," has been assigned to this variant. - |
HEXOSAMINIDASE B, HEAT-LABILE POLYMORPHISM Benign:1
Benign, no assertion criteria provided | literature only | OMIM | Jan 01, 1997 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at