15-72351132-C-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1_ModeratePM2PP3_StrongPP5_Very_Strong
The NM_000520.6(HEXA):c.672+1G>A variant causes a splice donor change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,433,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Consequence
NM_000520.6 splice_donor
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.672+1G>A | splice_donor_variant | ENST00000268097.10 | |||
HEXA | NM_001318825.2 | c.705+1G>A | splice_donor_variant | ||||
HEXA | NR_134869.3 | n.714+1G>A | splice_donor_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.672+1G>A | splice_donor_variant | 1 | NM_000520.6 | P1 | |||
ENST00000570175.1 | n.2486C>T | non_coding_transcript_exon_variant | 3/3 | 1 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251438Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135886
GnomAD4 exome AF: 0.00000488 AC: 7AN: 1433838Hom.: 0 Cov.: 27 AF XY: 0.00000699 AC XY: 5AN XY: 715296
GnomAD4 genome Cov.: 32
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:4
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 17, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Oct 21, 2020 | Variant summary: HEXA c.672+1G>A is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Four predict the variant abolishes a 5 splicing donor site. Consistent with this prediction, Akli et al report that this variant resulted in skipping of exon 6 and a reduction in HEXA mRNA levels by approximately 50% (Akli_1993). The variant allele was found at a frequency of 4e-06 in 251438 control chromosomes (gnomAD). c.672+1G>A has been reported in the literature in individuals affected with various forms (Juvenile/Adult, Late onset and Infantile acute) of Tay-Sachs Disease (Akli_1993, Maegawa_2007, Tanaka_2003). These data indicate that the variant may be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | May 10, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 05, 2024 | This sequence change affects a donor splice site in intron 6 of the HEXA gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs387906311, gnomAD 0.0009%). Disruption of this splice site has been observed in individual(s) with clinical features of hexosaminidase A deficiency (PMID: 14566483, 17015493). ClinVar contains an entry for this variant (Variation ID: 3928). Studies have shown that disruption of this splice site results in skipping of exon 6, but is expected to preserve the integrity of the reading-frame (PMID: 8490625). For these reasons, this variant has been classified as Pathogenic. - |
Tay-sachs disease, juvenile/adult Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 1993 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2016 | The c.672+1 G>A splice site variant in the HEXA gene has been previously reported in a patient with Tay-Sachs disease in whom a second variant in HEXA was not identified (Akli et al. 1993). cDNA and Northern blot analyses found that c.672+1 G>A results in skipping of exon 6 and a 50% reduction in HEXA mRNA levels (Akli et al. 1993). The c.672+1 G> variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. We interpret c.672+1 G> to be a pathogenic variant. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at