rs1553606128
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000404.4(GLB1):c.1510_1511insGA(p.Asn504ArgfsTer97) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,860 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. N504N) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GLB1
NM_000404.4 frameshift
NM_000404.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.0930
Publications
1 publications found
Genes affected
GLB1 (HGNC:4298): (galactosidase beta 1) This gene encodes a member of the glycosyl hydrolase 35 family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature lysosomal enzyme. This enzyme catalyzes the hydrolysis of a terminal beta-linked galactose residue from ganglioside substrates and other glycoconjugates. Mutations in this gene may result in GM1-gangliosidosis and Morquio B syndrome. [provided by RefSeq, Nov 2015]
GLB1 Gene-Disease associations (from GenCC):
- GM1 gangliosidosisInheritance: AR Classification: DEFINITIVE Submitted by: ClinGen, Myriad Women’s Health
- GM1 gangliosidosis type 3Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
- mucopolysaccharidosis type 4BInheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp
- GM1 gangliosidosis type 1Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
- GM1 gangliosidosis type 2Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
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 3-33014279-T-TTC is Pathogenic according to our data. Variant chr3-33014279-T-TTC is described in ClinVar as Pathogenic. ClinVar VariationId is 555117.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_000404.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLB1 | MANE Select | c.1510_1511insGA | p.Asn504ArgfsTer97 | frameshift | Exon 15 of 16 | NP_000395.3 | |||
| GLB1 | c.1654_1655insGA | p.Asn552ArgfsTer97 | frameshift | Exon 16 of 17 | NP_001303969.2 | ||||
| GLB1 | c.1420_1421insGA | p.Asn474ArgfsTer97 | frameshift | Exon 15 of 16 | NP_001073279.2 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| GLB1 | TSL:1 MANE Select | c.1510_1511insGA | p.Asn504ArgfsTer97 | frameshift | Exon 15 of 16 | ENSP00000306920.4 | P16278 | ||
| GLB1 | TSL:1 | c.1117_1118insGA | p.Asn373ArgfsTer97 | frameshift | Exon 12 of 13 | ENSP00000305920.8 | E7EQ29 | ||
| GLB1 | TSL:2 | c.1420_1421insGA | p.Asn474ArgfsTer97 | frameshift | Exon 15 of 16 | ENSP00000382333.2 | P16278 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461860Hom.: 0 Cov.: 35 AF XY: 0.00 AC XY: 0AN XY: 727228 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1461860
Hom.:
Cov.:
35
AF XY:
AC XY:
0
AN XY:
727228
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33480
American (AMR)
AF:
AC:
0
AN:
44724
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26136
East Asian (EAS)
AF:
AC:
0
AN:
39700
South Asian (SAS)
AF:
AC:
0
AN:
86248
European-Finnish (FIN)
AF:
AC:
0
AN:
53416
Middle Eastern (MID)
AF:
AC:
0
AN:
5764
European-Non Finnish (NFE)
AF:
AC:
1
AN:
1111998
Other (OTH)
AF:
AC:
0
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
Heterozygous variant carriers
0
0
1
1
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2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Age Distribution
Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
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50-55
55-60
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>80
Age
GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
1
-
-
GLB1-related disorder (1)
1
-
-
GM1 gangliosidosis;C0086652:Mucopolysaccharidosis, MPS-IV-B (1)
1
-
-
Mucopolysaccharidosis, MPS-IV-B;C0268271:Infantile GM1 gangliosidosis;C0268272:GM1 gangliosidosis type 2;C0268273:GM1 gangliosidosis type 3 (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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