chr15-72346650-CCTT-C
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Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PM4_Supporting
The NM_000520.6(HEXA):βc.1204_1206delβ(p.Lys402del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000372 in 1,613,980 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (β β ).
Frequency
Genomes: π 0.000013 ( 0 hom., cov: 30)
Exomes π: 0.0000027 ( 0 hom. )
Consequence
HEXA
NM_000520.6 inframe_deletion
NM_000520.6 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.896
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 Uncertain_significance. Variant got 3 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PM4
Nonframeshift variant in NON repetitive region in NM_000520.6. Strenght limited to Supporting due to length of the change: 1aa.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
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HEXA | NM_000520.6 | c.1204_1206del | p.Lys402del | inframe_deletion | 11/14 | ENST00000268097.10 | |
HEXA | NM_001318825.2 | c.1237_1239del | p.Lys413del | inframe_deletion | 11/14 | ||
HEXA | NR_134869.3 | n.1116-328_1116-326del | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.1204_1206del | p.Lys402del | inframe_deletion | 11/14 | 1 | NM_000520.6 | P1 | |
ENST00000570175.1 | n.1432_1434del | non_coding_transcript_exon_variant | 2/3 | 1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000159 AC: 4AN: 251480Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135914
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461776Hom.: 0 AF XY: 0.00000275 AC XY: 2AN XY: 727194
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152204Hom.: 0 Cov.: 30 AF XY: 0.0000269 AC XY: 2AN XY: 74350
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tay-Sachs disease Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Mar 18, 2022 | ClinVar contains an entry for this variant (Variation ID: 554678). This variant has been observed in individual(s) with Tay-Sachs disease (PMID: 9150157). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant, c.1204_1206del, results in the deletion of 1 amino acid(s) of the HEXA protein (p.Lys402del), but otherwise preserves the integrity of the reading frame. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 16, 2021 | NM_000520.4(HEXA):c.1204_1206delAAG(K402del) is an in-frame deletion variant classified as a variant of uncertain significance in the context of hexosaminidase A deficiency. K402del has not been observed in cases with relevant disease. Functional assessments of this variant are not available in the literature. K402del has been observed in population frequency databases (gnomAD: NFE <0.001%). In summary, there is insufficient evidence to classify NM_000520.4(HEXA):c.1204_1206delAAG(K402del) as pathogenic or benign. Please note: this variant was assessed in the context of healthy population screening. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at