chrX-101401703-A-C
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PM5PP3_StrongPP5_Moderate
The NM_000169.3(GLA):c.476T>G(p.Phe159Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F159L) has been classified as Uncertain significance.
Frequency
Consequence
NM_000169.3 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 12 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.476T>G | p.Phe159Cys | missense_variant | 3/7 | ENST00000218516.4 | |
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+6246A>C | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.476T>G | p.Phe159Cys | missense_variant | 3/7 | 1 | NM_000169.3 | P1 |
Frequencies
GnomAD3 genomes Cov.: 23
GnomAD4 exome Cov.: 29
GnomAD4 genome Cov.: 23
ClinVar
Submissions by phenotype
Fabry disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 10, 2017 | This variant has been observed in an individual affected with Fabry disease and confirmed low GLA enzymatic activity (Invitae). In summary, this variant is a novel missense change that has been observed in an affected individual with confirmed biochemical results characteristic of this condition. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is not present in population databases (ExAC no frequency). This sequence change replaces phenylalanine with cysteine at codon 159 of the GLA protein (p.Phe159Cys). The phenylalanine residue is highly conserved and there is a large physicochemical difference between phenylalanine and cysteine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at