15-72375972-T-G
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate
The NM_000520.6(HEXA):āc.1A>Cā(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (ā ).
Frequency
Consequence
NM_000520.6 initiator_codon
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.43A>C | non_coding_transcript_exon_variant | Exon 1 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1A>C | p.Met1? | initiator_codon_variant | Exon 1 of 14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.1A>C | non_coding_transcript_exon_variant | Exon 1 of 16 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000400 AC: 1AN: 249732Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135252
GnomAD4 exome AF: 0.00000205 AC: 3AN: 1461130Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 726868
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:2
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This sequence change affects the initiator methionine of the HEXA mRNA. The next in-frame methionine is located at codon 193. This variant is present in population databases (rs121907965, gnomAD 0.0009%). Disruption of the initiator codon has been observed in individual(s) with Tay-Sachs disease (PMID: 9153525; Invitae). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 619221). This variant disrupts the c.1A nucleotide in the HEXA gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 1532289, 21796138). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at