chr15-72349093-A-T
Variant summary
Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5
The NM_000520.6(HEXA):c.972T>A(p.Val324Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Consequence
NM_000520.6 synonymous
Scores
Clinical Significance
Conservation
Publications
- Tay-Sachs diseaseInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), ClinGen
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ACMG classification
Our verdict: Uncertain_significance. The variant received 5 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.972T>A | p.Val324Val | synonymous_variant | Exon 8 of 14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1005T>A | p.Val335Val | synonymous_variant | Exon 8 of 14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.1014T>A | non_coding_transcript_exon_variant | Exon 8 of 11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.972T>A | p.Val324Val | synonymous_variant | Exon 8 of 14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.413-2768T>A | intron_variant | Intron 3 of 15 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 show subpopulations
GnomAD4 exome Cov.: 31
GnomAD4 genome AF: 0.00000657 AC: 1AN: 152206Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74358 show subpopulations ⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.
Age Distribution
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:1Uncertain:1
Variant summary: HEXA c.972T>A alters a conserved nucleotide resulting in a synonymous change. Several computational tools predict a significant impact on normal splicing: Three predict the variant creates a 5 donor site in exon 8 located 17 base pairs upstream of the canonical intron 8 splice donor site. The variant was absent in 251352 control chromosomes. c.972T>A has been reported in the literature in at-least one compound heterozygous individual affected with GM2-gangliosidosis (example: Wicklow_2004). At least one publication reports experimental evidence that this variant affects mRNA splicing. Specifically, bioinformatics prediction of utilization of the alternate donor site was confirmed using cDNA from this affected individual and consisted of both normal and short transcript (example: Wicklow_2004). Authors state that RT/PCR analyses confirmed the presence of low levels of abnormal transcript in proband fibroblasts that contained a premature stop codon in the mRNA at a position equivalent to amino acid 340, and therefore rapid decay of the transcript via NMD. Sequencing of this abnormal transcript revealed a 17 base pair deletion due to the usage of the novel upstream splice donor site in exon 8. The following publication has been ascertained in the context of this evaluation (PMID: 15108204). ClinVar contains an entry for this variant (Variation ID: 3943). Based on the evidence outlined above, the variant was classified as likely pathogenic. -
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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 3943). This variant has been observed in individual(s) with hexosaminidase A deficiency (PMID: 15108204). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change affects codon 324 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein. -
Gm2-gangliosidosis, subacute Pathogenic:1
- -
not provided Pathogenic:1
Not observed at significant frequency in large population cohorts (gnomAD); Published functional studies and in silico splice prediction algorithms suggest a damaging effect resulting in aberrant splicing (Wicklow et al., 2004); This variant is associated with the following publications: (PMID: 35936646, 15108204) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at