rs1554034452
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000521.4(HEXB):c.146C>A(p.Ser49*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000188 in 1,596,540 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
HEXB
NM_000521.4 stop_gained
NM_000521.4 stop_gained
Scores
1
6
Clinical Significance
Conservation
PhyloP100: -1.46
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 5-74685406-C-A is Pathogenic according to our data. Variant chr5-74685406-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 555683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
HEXB | NM_000521.4 | c.146C>A | p.Ser49* | stop_gained | 1/14 | ENST00000261416.12 | NP_000512.2 | |
HEXB | NM_001292004.2 | c.-376-3922C>A | intron_variant | NP_001278933.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
HEXB | ENST00000261416.12 | c.146C>A | p.Ser49* | stop_gained | 1/14 | 1 | NM_000521.4 | ENSP00000261416.7 | ||
HEXB | ENST00000511181.5 | c.-376-3922C>A | intron_variant | 1 | ENSP00000426285.1 | |||||
HEXB | ENST00000513079.5 | n.211C>A | non_coding_transcript_exon_variant | 1/6 | 2 | |||||
HEXB | ENST00000515528.1 | n.201C>A | non_coding_transcript_exon_variant | 1/2 | 2 |
Frequencies
GnomAD3 genomes AF: 0.00000660 AC: 1AN: 151528Hom.: 0 Cov.: 31
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GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445012Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 718016
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GnomAD4 genome AF: 0.00000660 AC: 1AN: 151528Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 73988
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ClinVar
Significance: Pathogenic/Likely 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 | Labcorp Genetics (formerly Invitae), Labcorp | Apr 26, 2020 | For these reasons, this variant has been classified as Pathogenic. Loss-of-function variants in HEXB are known to be pathogenic (PMID: 7550345, 18758829). This variant has been observed in individual(s) with Sandhoff disease (PMID: 22848519). ClinVar contains an entry for this variant (Variation ID: 555683). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Ser49*) in the HEXB gene. It is expected to result in an absent or disrupted protein product. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Dec 28, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jan 10, 2019 | Variant summary: HEXB c.146C>A (p.Ser49X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation downstream of this position has been classified as pathogenic by our laboratory (eg. c.850C>T (p.Arg284X)). The variant was absent in 204176 control chromosomes (gnomAD). c.146C>A has been reported in the literature in one homozygous individual affected with Sandhoff Disease while, experimental evidence evaluating an impact on protein function demostrated a residual enzymatic activity of 1.6% compared to normal control (Zampieri_2012). A ClinVar submission from a clinical diagnostic laboratory (evaluation after 2014) cites the variant as likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. - |
Computational scores
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Name
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BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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