rs886044829
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_000169.3(GLA):c.1057_1058del(p.Met353AspfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★★).
Frequency
Genomes: not found (cov: 23)
Consequence
GLA
NM_000169.3 frameshift
NM_000169.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.85
Genes affected
GLA (HGNC:4296): (galactosidase alpha) This gene encodes a homodimeric glycoprotein that hydrolyses the terminal alpha-galactosyl moieties from glycolipids and glycoproteins. This enzyme predominantly hydrolyzes ceramide trihexoside, and it can catalyze the hydrolysis of melibiose into galactose and glucose. A variety of mutations in this gene affect the synthesis, processing, and stability of this enzyme, which causes Fabry disease, a rare lysosomal storage disorder that results from a failure to catabolize alpha-D-galactosyl glycolipid moieties. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 55 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-101398040-CAT-C is Pathogenic according to our data. Variant chrX-101398040-CAT-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 284485.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398040-CAT-C is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.1057_1058del | p.Met353AspfsTer21 | frameshift_variant | 7/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+2585_300+2586del | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.1057_1058del | p.Met353AspfsTer21 | frameshift_variant | 7/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD3 genomes
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome Cov.: 23
GnomAD4 genome
Cov.:
23
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Fabry disease Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jun 24, 2021 | For these reasons, this variant has been classified as Pathogenic. This variant disrupts the C-terminus of the GLA protein. Other variant(s) that disrupt this region (p.Tyr397Metfs*7) have been determined to be pathogenic (PMID: 10666480). This suggests that variants that disrupt this region of the protein are likely to be causative of disease. This variant has been observed in individual(s) with Fabry disease (PMID: 9100224). ClinVar contains an entry for this variant (Variation ID: 284485). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Met353Aspfs*21) in the GLA gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 77 amino acid(s) of the GLA protein. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jul 15, 2021 | - - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jun 02, 2016 | Variant summary: The GLA c.1057_1058delAT (p.Met353Aspfs) variant results in a premature termination codon, predicted to cause a truncated or absent GLA protein, which are commonly known mechanisms for disease. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in one affected individual via a publication. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Probable Disease Variant/Likely Pathogenic," until additional information becomes available. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Oct 30, 2015 | - - |
Computational scores
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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