rs76075374
Positions:
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBS1_SupportingBS2
The NM_000520.6(HEXA):c.*575G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0137 in 154,014 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.014 ( 22 hom., cov: 33)
Exomes 𝑓: 0.021 ( 1 hom. )
Consequence
HEXA
NM_000520.6 3_prime_UTR
NM_000520.6 3_prime_UTR
Scores
2
Clinical Significance
Conservation
PhyloP100: -0.147
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 Benign. Variant got -9 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.76).
BS1
?
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0136 (2067/152182) while in subpopulation NFE AF= 0.0219 (1487/67992). AF 95% confidence interval is 0.0209. There are 22 homozygotes in gnomad4. There are 1008 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
BS2
?
High Homozygotes in GnomAd4 at 22 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXA | NM_000520.6 | c.*575G>A | 3_prime_UTR_variant | 14/14 | ENST00000268097.10 | ||
HEXA | NM_001318825.2 | c.*575G>A | 3_prime_UTR_variant | 14/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXA | ENST00000268097.10 | c.*575G>A | 3_prime_UTR_variant | 14/14 | 1 | NM_000520.6 | P1 | ||
ENST00000570175.1 | n.166-1884C>T | intron_variant, non_coding_transcript_variant | 1 |
Frequencies
GnomAD3 genomes ? AF: 0.0136 AC: 2068AN: 152064Hom.: 22 Cov.: 33
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GnomAD4 exome AF: 0.0213 AC: 39AN: 1832Hom.: 1 Cov.: 0 AF XY: 0.0154 AC XY: 15AN XY: 974
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GnomAD4 genome ? AF: 0.0136 AC: 2067AN: 152182Hom.: 22 Cov.: 33 AF XY: 0.0135 AC XY: 1008AN XY: 74414
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Tay-Sachs disease Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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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