rs146938346
Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate
The NM_000520.6(HEXA):āc.10T>Cā(p.Ser4Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000216 in 1,613,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ). Synonymous variant affecting the same amino acid position (i.e. S4S) has been classified as Likely benign.
Frequency
Consequence
NM_000520.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 0 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.10T>C | p.Ser4Pro | missense_variant | 1/14 | ENST00000268097.10 | |
HEXA | NM_001318825.2 | c.10T>C | p.Ser4Pro | missense_variant | 1/14 | ||
HEXA | NR_134869.3 | n.52T>C | non_coding_transcript_exon_variant | 1/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.10T>C | p.Ser4Pro | missense_variant | 1/14 | 1 | NM_000520.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000989 AC: 15AN: 151652Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000140 AC: 35AN: 250380Hom.: 0 AF XY: 0.0000959 AC XY: 13AN XY: 135502
GnomAD4 exome AF: 0.000229 AC: 334AN: 1461494Hom.: 0 Cov.: 30 AF XY: 0.000223 AC XY: 162AN XY: 727048
GnomAD4 genome ? AF: 0.0000989 AC: 15AN: 151652Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6AN XY: 74056
ClinVar
Submissions by phenotype
Tay-Sachs disease Uncertain:5
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 27, 2022 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 31, 2019 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Counsyl | Nov 14, 2017 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2022 | This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 4 of the HEXA protein (p.Ser4Pro). This variant is present in population databases (rs146938346, gnomAD 0.03%). This missense change has been observed in individual(s) with hexosaminidase A deficiency (PMID: 15108204). ClinVar contains an entry for this variant (Variation ID: 554702). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects HEXA function (PMID: 15108204, 20363167). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Feb 09, 2022 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Feb 16, 2023 | Variant summary: HEXA c.10T>C (p.Ser4Pro) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00014 in 250380 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in HEXA causing Tay-Sachs Disease (0.00014 vs 0.0014), allowing no conclusion about variant significance. c.10T>C has been reported in the literature an individual affected with the Tay-Sachs Disease variant GM2 gangliosidosis (Wicklow_2004), however 2 other pathogenic variants were determined to be the cause of disease in the patient. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in 59% of normal activity (Wicklow_2004). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as VUS-possibly benign. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | May 02, 2024 | In silico analysis indicates that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 15108204, 20363167, 35936646) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at