rs1554034452
Variant names:
Your query was ambiguous. Multiple possible variants found:
Variant summary
Our verdict is Pathogenic. The variant received 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 Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. S49S) has been classified as Likely benign. 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
5
Clinical Significance
Conservation
PhyloP100: -1.46
Publications
1 publications found
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]
HEXB Gene-Disease associations (from GenCC):
- Sandhoff diseaseInheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Myriad Women’s Health, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 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 Pathogenic. ClinVar VariationId is 555683.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000521.4. You can select a different transcript below to see updated ACMG assignments.
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| HEXB | TSL:1 MANE Select | c.146C>A | p.Ser49* | stop_gained | Exon 1 of 14 | ENSP00000261416.7 | P07686 | ||
| HEXB | TSL:1 | c.-376-3922C>A | intron | N/A | ENSP00000426285.1 | Q5URX0 | |||
| HEXB | TSL:2 | n.211C>A | non_coding_transcript_exon | Exon 1 of 6 |
Frequencies
GnomAD3 genomes 0.00000660 AC: 1AN: 151528Hom.: 0 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
1
AN:
151528
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 0.00000138 AC: 2AN: 1445012Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1AN XY: 718016 show subpopulations
GnomAD4 exome
AF:
AC:
2
AN:
1445012
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
718016
show subpopulations
African (AFR)
AF:
AC:
0
AN:
32800
American (AMR)
AF:
AC:
0
AN:
42614
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
25820
East Asian (EAS)
AF:
AC:
0
AN:
38100
South Asian (SAS)
AF:
AC:
0
AN:
84770
European-Finnish (FIN)
AF:
AC:
0
AN:
49556
Middle Eastern (MID)
AF:
AC:
0
AN:
5748
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1105950
Other (OTH)
AF:
AC:
1
AN:
59654
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.500
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
GnomAD4 genome 0.00000660 AC: 1AN: 151528Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1AN XY: 73988 show subpopulations
GnomAD4 genome
AF:
AC:
1
AN:
151528
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
73988
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41252
American (AMR)
AF:
AC:
0
AN:
15212
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5100
South Asian (SAS)
AF:
AC:
0
AN:
4752
European-Finnish (FIN)
AF:
AC:
0
AN:
10582
Middle Eastern (MID)
AF:
AC:
0
AN:
314
European-Non Finnish (NFE)
AF:
AC:
1
AN:
67858
Other (OTH)
AF:
AC:
0
AN:
2078
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
Hom.:
Bravo
AF:
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
3
-
-
Sandhoff disease (3)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
PhyloP100
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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