rs727504773
Variant summary
Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_StrongPM2PP3PP5_Moderate
The NM_000169.3(GLA):c.802-3_804delinsGGCAACTTT variant causes a splice acceptor, coding sequence, intron change involving the alteration of a conserved nucleotide. 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 splice_acceptor, coding_sequence, intron
NM_000169.3 splice_acceptor, coding_sequence, intron
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.32
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]
Genome browser will be placed here
ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 9 ACMG points.
PVS1
?
Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.15271318 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 26, new splice context is: attggcaactttggcctcAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant X-101398565-TAACTG-AAAGTTGCC is Pathogenic according to our data. Variant chrX-101398565-TAACTG-AAAGTTGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179299.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLA | NM_000169.3 | c.802-3_804delinsGGCAACTTT | splice_acceptor_variant, coding_sequence_variant, intron_variant | 6/7 | ENST00000218516.4 | ||
RPL36A-HNRNPH2 | NM_001199973.2 | c.300+3108_300+3113delinsAAAGTTGCC | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLA | ENST00000218516.4 | c.802-3_804delinsGGCAACTTT | splice_acceptor_variant, coding_sequence_variant, intron_variant | 6/7 | 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: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Fabry disease Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Sep 19, 2013 | The 802-3_804delinsGGCAACTTT variant in GLA has not been previously reported in individuals with cardiomyopathy or Fabry disease. Data from large population stu dies is insufficient to assess the frequency of this variant. This variant is lo cated in a 3' splice region and alters the invariant region (+/- 1,2) of the spl ice consensus. This is predicted to cause altered splicing leading to an abnorma l or absent protein. Variants in GLA are strongly associated with Fabry disease , an X-linked lysosomal storage disorder, which may present as isolated HCM (Bee r 2002). In summary, this variant is likely to be pathogenic, but additional stu dies are needed to fully establish its clinical significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at