chr15-72346552-G-A
Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 10P and 2B. PM2PP5_Very_StrongBP4BP7
The NM_000520.6(HEXA):c.1305C>T(p.Tyr435Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000397 in 1,613,896 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 Likely pathogenic (★★).
Frequency
Consequence
NM_000520.6 synonymous
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 rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.1305C>T | p.Tyr435Tyr | synonymous_variant | Exon 11 of 14 | ENST00000268097.10 | NP_000511.2 | |
HEXA | NM_001318825.2 | c.1338C>T | p.Tyr446Tyr | synonymous_variant | Exon 11 of 14 | NP_001305754.1 | ||
HEXA | NR_134869.3 | n.1116-227C>T | intron_variant | Intron 9 of 10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1305C>T | p.Tyr435Tyr | synonymous_variant | Exon 11 of 14 | 1 | NM_000520.6 | ENSP00000268097.6 | ||
ENSG00000260729 | ENST00000379915.4 | n.413-227C>T | intron_variant | Intron 3 of 15 | 2 | ENSP00000478716.1 |
Frequencies
GnomAD3 genomes AF: 0.0000986 AC: 15AN: 152164Hom.: 0 Cov.: 30
GnomAD3 exomes AF: 0.0000796 AC: 20AN: 251370Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135882
GnomAD4 exome AF: 0.0000335 AC: 49AN: 1461732Hom.: 0 Cov.: 34 AF XY: 0.0000234 AC XY: 17AN XY: 727160
GnomAD4 genome AF: 0.0000986 AC: 15AN: 152164Hom.: 0 Cov.: 30 AF XY: 0.000121 AC XY: 9AN XY: 74310
ClinVar
Submissions by phenotype
Tay-Sachs disease Pathogenic:6
This sequence change affects codon 435 of the HEXA mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the HEXA protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (rs587779406, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This variant has been observed in individual(s) with juvenile Tay-Sachs disease (PMID: 20363167, 22789865, 24767253, 25606403). 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: 100729). Studies have shown that this variant results in skipping of exons 9-12 and introduces a premature termination codon (PMID: 20363167). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -
This synonymous variant affects a weakly conserved nucleotide in exon 11 of 14 and is predicted to affect an exonic splicing enhancer site. Functional evidence suggests this variant may lead to exon 11 skipping and is likely to interfere with normal splicing (PMID: 20363167). This variant has been previously reported as a compound heterozygous change in patients with juvenile Tay-Sachs disease, Tay-Sachs disease, and juvenile type 2 gangliosidosis (PMID 24767253, 20363167, 22789865, 25606403). The c.1305C>T (p.Tyr435=) variant is present in the heterozygous state in the gnomAD population database at a frequency of 0.008% (24/282766) and is absent in the homozygous state. Based on the available evidence, the c.1305C>T (p.Tyr435=) variant is classified as Likely Pathogenic. -
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Variant summary: HEXA c.1305C>T alters a conserved nucleotide resulting in a synonymous change. Computational tools predict a significant impact on normal splicing, particularly that the variant disrupts/abolishes an exonic splicing enhancer site. Experimental evidence supports these predictions demonstrating the variant leads to complete absence of the normal transcript and formation of aberrant transcripts (Levit_2010). The variant allele was found at a frequency of 8e-05 in 251370 control chromosomes (gnomAD). This frequency is not higher than expected for a pathogenic variant in HEXA causing Tay-Sachs Disease (8e-05 vs 0.0014), allowing no conclusion about variant significance. c.1305C>T has been reported in the literature in compound heterozygous individuals affected with Tay-Sachs Disease (e.g. Levit_2010, Gort_2012, Fernandez-Marmiesse_2014, Georgiou_2014). These data indicate that the variant is likely to be associated with disease. One of the affected compound heterozygous individuals was noted with severe Hex A deficiency in the range known for patients suffering from TSD (4-10% Hex A). However, the enzymatic activity of the variant protein expressed in TSD glial cell-line as measured with 4-MUG as a substrate, was similar to that of wild-type (Levit_2010). Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as likely pathogenic. -
Inborn genetic diseases Pathogenic:1
The c.1305C>T (p.Y435Y) alteration is located in coding exon 11 of the HEXA gene. This alteration consists of a C to T substitution at nucleotide position 1305. This nucleotide substitution does not change the amino acid at codon 435. However, further evidence has suggested this nucleotide change is deleterious. Based on data from gnomAD, the T allele has an overall frequency of 0.009% (24/282766) total alleles studied. The highest observed frequency was 0.048% (17/35436) of Latino alleles. This alteration was detected in conjunction with another alteration in HEXA, in multiple individuals with Tay-Sachs disease (Gort, 2012; Fernandez-Marmiesse, 2014; Georgiou, 2014). This nucleotide position is well conserved in available vertebrate species. In an assay testing HEXA function, this variant showed a functionally abnormal result (Levit, 2010). In silico splice site analysis for this alteration is inconclusive. Based on the available evidence, this alteration is classified as pathogenic. -
Leukodystrophy;C0036572:Seizure;C1384666:Hearing impairment Pathogenic:1
ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 moderate -
not provided Pathogenic:1
This variant is associated with the following publications: (PMID: 20363167, 25606403, 22789865) -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at