rs762060470
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong
The NM_000520.6(HEXA):c.459+5G>A variant causes a splice donor 5th base, intron change. The variant allele was found at a frequency of 0.000018 in 1,609,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
HEXA
NM_000520.6 splice_donor_5th_base, intron
NM_000520.6 splice_donor_5th_base, intron
Scores
1
1
Splicing: ADA: 1.000
2
Clinical Significance
Conservation
PhyloP100: 5.18
Genes affected
HEXA (HGNC:4878): (hexosaminidase subunit alpha) This gene encodes a member of the glycosyl hydrolase 20 family of proteins. The encoded preproprotein is proteolytically processed to generate the alpha subunit of the lysosomal enzyme beta-hexosaminidase. This enzyme, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Mutations in this gene lead to an accumulation of GM2 ganglioside in neurons, the underlying cause of neurodegenerative disorders termed the GM2 gangliosidoses, including Tay-Sachs disease (GM2-gangliosidosis type I). Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. [provided by RefSeq, Jan 2016]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
?
Variant 15-72353686-C-T is Pathogenic according to our data. Variant chr15-72353686-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 374505.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.459+5G>A | splice_donor_5th_base_variant, intron_variant | ENST00000268097.10 | |||
HEXA | NM_001318825.2 | c.492+5G>A | splice_donor_5th_base_variant, intron_variant | ||||
HEXA | NR_134869.3 | n.501+5G>A | splice_donor_5th_base_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.459+5G>A | splice_donor_5th_base_variant, intron_variant | 1 | NM_000520.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000788 AC: 12AN: 152218Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251424Hom.: 0 AF XY: 0.0000221 AC XY: 3AN XY: 135880
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GnomAD4 exome AF: 0.0000117 AC: 17AN: 1457112Hom.: 0 Cov.: 29 AF XY: 0.0000110 AC XY: 8AN XY: 725270
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GnomAD4 genome ? AF: 0.0000788 AC: 12AN: 152218Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6AN XY: 74382
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tay-Sachs disease Pathogenic:6
Pathogenic, criteria provided, single submitter | research | HudsonAlpha Institute for Biotechnology, HudsonAlpha Institute for Biotechnology | Feb 09, 2017 | - - |
Pathogenic, no assertion criteria provided | research | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Sep 22, 2012 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 08, 2017 | Variant summary: The HEXA c.459+5G>A (aka IVS4+5G>A) is a splice-site variant that alters a highly conserved nucleotide. One in silico tool predicts a damaging outcome for this variant. 5/5 in silico tools via Alamut predict this variant to disrupt a canonical donor sequence, with functional studies confirming that this variant leads to exon 4 skipping and NMD. The variant is present in control datasets of ExAC and gnomAD at a low frequency of 0.000028 (3/120932 and 8/ 277156 chrs tested, respectively). The observed frequency does not exceed the maximum expected allele frequency for a pathogenic variant of 0.0013. The variant has been reported in affected individuals with confirmed Tay-Sachs disease via publications and is cited as Pathogenic/Likely Pathogenic by a reputable database/clinical laboratories. Taken together, this variant is classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Mar 08, 2022 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Mar 16, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 14, 2023 | This sequence change falls in intron 4 of the HEXA gene. It does not directly change the encoded amino acid sequence of the HEXA protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs762060470, gnomAD 0.02%). This variant has been observed in individuals with Tay-Sachs disease (PMID: 1837283, 22441121, 22789865, 27896118). It is commonly reported in individuals of Spanish and Argentinian ancestry (PMID: 1837283, 22441121, 22789865, 27896118). This variant is also known as IVS4+5G>A. ClinVar contains an entry for this variant (Variation ID: 374505). 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. For these reasons, this variant has been classified as Pathogenic. - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 07, 2022 | Intronic +5 splice site variant in a gene for which loss-of-function is a known mechanism of disease, and functional analysis found this variant results in abnormal splicing (Akli et al., 1991); This variant is associated with the following publications: (PMID: 8044648, 27896118, 22441121, 25525159, 1837283, 9150157, 22723944, 24498621, 22789865, 34426522) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2017 | - - |
Computational scores
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Name
Calibrated prediction
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Prediction
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
Splicing
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Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 5
Find out detailed SpliceAI scores and Pangolin per-transcript scores at