rs1555987101

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2PM5PP3_StrongPP5

The NM_000169.3(GLA):​c.141G>C​(p.Trp47Cys) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. W47G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

GLA
NM_000169.3 missense

Scores

15
2
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 7.68
Variant links:
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]
RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
PP5
Variant X-101407763-C-G is Pathogenic according to our data. Variant chrX-101407763-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 524213.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLANM_000169.3 linkuse as main transcriptc.141G>C p.Trp47Cys missense_variant 1/7 ENST00000218516.4 NP_000160.1 P06280Q53Y83

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLAENST00000218516.4 linkuse as main transcriptc.141G>C p.Trp47Cys missense_variant 1/71 NM_000169.3 ENSP00000218516.4 P06280
RPL36A-HNRNPH2ENST00000409170.3 linkuse as main transcriptc.301-4173C>G intron_variant 4 ENSP00000386655.4 H7BZ11

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Fabry disease Pathogenic:1
Pathogenic, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpOct 15, 2021For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Trp47 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11668641, 27211852). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. 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. This missense change has been observed in individual(s) with Fabry disease (Invitae). It has also been observed to segregate with disease in related individuals. This variant is not present in population databases (ExAC no frequency). This sequence change replaces tryptophan with cysteine at codon 47 of the GLA protein (p.Trp47Cys). The tryptophan residue is highly conserved and there is a large physicochemical difference between tryptophan and cysteine. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityMay 26, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.98
CardioboostCm
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.73
D
BayesDel_noAF
Pathogenic
0.82
CADD
Pathogenic
32
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;.
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
1.0
D;D
M_CAP
Pathogenic
0.96
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Pathogenic
0.95
D
MutationAssessor
Pathogenic
4.6
H;.
PrimateAI
Uncertain
0.63
T
PROVEAN
Pathogenic
-11
D;.
REVEL
Pathogenic
0.96
Sift
Pathogenic
0.0
D;.
Sift4G
Pathogenic
0.0010
D;.
Polyphen
1.0
D;.
Vest4
0.99
MutPred
0.91
Loss of helix (P = 0.1299);Loss of helix (P = 0.1299);
MVP
1.0
MPC
2.2
ClinPred
1.0
D
GERP RS
5.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.98
gMVP
1.0

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555987101; hg19: chrX-100662751; API