rs761117459
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000521.4(HEXB):c.333G>A(p.Trp111Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,782 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
HEXB
NM_000521.4 stop_gained
NM_000521.4 stop_gained
Scores
3
4
Clinical Significance
Conservation
PhyloP100: 0.721
Genes affected
HEXB (HGNC:4879): (hexosaminidase subunit beta) Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2014]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
?
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 5-74689361-G-A is Pathogenic according to our data. Variant chr5-74689361-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 557986.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
HEXB | NM_000521.4 | c.333G>A | p.Trp111Ter | stop_gained | 2/14 | ENST00000261416.12 | |
HEXB | NM_001292004.2 | c.-343G>A | 5_prime_UTR_variant | 2/14 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.333G>A | p.Trp111Ter | stop_gained | 2/14 | 1 | NM_000521.4 | P1 | |
HEXB | ENST00000511181.5 | c.-343G>A | 5_prime_UTR_variant | 2/14 | 1 | ||||
HEXB | ENST00000513079.5 | n.398G>A | non_coding_transcript_exon_variant | 2/6 | 2 | ||||
HEXB | ENST00000515528.1 | n.388G>A | non_coding_transcript_exon_variant | 2/2 | 2 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251416Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135868
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1460782Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2AN XY: 726704
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GnomAD4 genome ? Cov.: 33
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Sandhoff disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics | Dec 26, 2022 | A compound heterozygous status for the variant c.333G>A in Exon 2 of the HEXB gene was detected. The variants have not been reported in the 1000 genomes database and has a MAF of 0.0008% in the gnomAD database. The in-silico prediction is disease causing by Mutation Taster and DANN. In summary, the variant meets our criteria to be classified as pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Apr 24, 2022 | This sequence change creates a premature translational stop signal (p.Trp111*) in the HEXB gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant is present in population databases (rs761117459, gnomAD 0.007%). This premature translational stop signal has been observed in individual(s) with Sandhoff disease (PMID: 26582265). ClinVar contains an entry for this variant (Variation ID: 557986). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Apr 25, 2018 | - - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
MutationTaster
Benign
A;N
Vest4
GERP RS
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