rs762374961
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate
The NM_000520.6(HEXA):c.1421G>T(p.Trp474Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,612,718 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W474C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000520.6 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 8 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1421G>T | p.Trp474Leu | missense_variant, splice_region_variant | 12/14 | ENST00000268097.10 | |
HEXA | NM_001318825.2 | c.1454G>T | p.Trp485Leu | missense_variant, splice_region_variant | 12/14 | ||
HEXA | NR_134869.3 | n.1206G>T | splice_region_variant, non_coding_transcript_exon_variant | 10/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1421G>T | p.Trp474Leu | missense_variant, splice_region_variant | 12/14 | 1 | NM_000520.6 | P1 | |
ENST00000570175.1 | n.1015C>A | non_coding_transcript_exon_variant | 2/3 | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1460592Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726646
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152126Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74304
ClinVar
Submissions by phenotype
Tay-Sachs disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 25, 2022 | This sequence change affects codon 474 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein. This variant also falls at the last nucleotide of exon 12, which is part of the consensus splice site for this exon. This variant is present in population databases (rs762374961, gnomAD 0.007%). This variant has not been reported in the literature in individuals affected with HEXA-related conditions. 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: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at