X-101397870-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_000169.3(GLA):​c.1229C>A​(p.Thr410Lys) variant causes a missense change. 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 (★).

Frequency

Genomes: not found (cov: 23)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control

Consequence

GLA
NM_000169.3 missense

Scores

8
8
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 6.94
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 8 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.982
PP5
Variant X-101397870-G-T is Pathogenic according to our data. Variant chrX-101397870-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 180833.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101397870-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLANM_000169.3 linkc.1229C>A p.Thr410Lys missense_variant 7/7 ENST00000218516.4 NP_000160.1 P06280Q53Y83

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLAENST00000218516.4 linkc.1229C>A p.Thr410Lys missense_variant 7/71 NM_000169.3 ENSP00000218516.4 P06280
RPL36A-HNRNPH2ENST00000409170.3 linkc.300+2413G>T intron_variant 4 ENSP00000386655.4 H7BZ11

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
0.00
AC:
0
AN:
1093038
Hom.:
0
Cov.:
30
AF XY:
0.00
AC XY:
0
AN XY:
358558
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
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 submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpNov 06, 2020Variant summary: GLA c.1229C>A (p.Thr410Lys) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta sandwich domain (IPR035373) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function consistent with in-silico tools specifically derived for assessment of GLA mutations that report a damaging outcome (example, Riera_2015). Other missense variants at the same codon have been reported in patients with Fabry disease supporting a mutational hotspot and/or critical and well established functional domain in the GLA protein. The variant was absent in 183422 control chromosomes. c.1229C>A has been reported in the literature in at-least one individual affected with Fabry Disease (example, Ashley_2001). These data do not allow any conclusion about variant significance. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect as the primary data supporting this evidence were not reported by the authors (Ashley_2001). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.43
CardioboostCm
Uncertain
0.11
BayesDel_addAF
Pathogenic
0.55
D
BayesDel_noAF
Pathogenic
0.56
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Pathogenic
0.97
D;.
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;D
M_CAP
Pathogenic
0.92
D
MetaRNN
Pathogenic
0.98
D;D
MetaSVM
Pathogenic
1.1
D
MutationAssessor
Uncertain
2.5
M;.
PrimateAI
Benign
0.39
T
PROVEAN
Uncertain
-2.9
D;.
REVEL
Pathogenic
0.82
Sift
Uncertain
0.0030
D;.
Sift4G
Uncertain
0.0060
D;.
Polyphen
0.96
D;.
Vest4
0.87
MutPred
0.89
Gain of ubiquitination at T410 (P = 0.0289);.;
MVP
1.0
MPC
1.5
ClinPred
0.98
D
GERP RS
5.4
Varity_R
0.98
gMVP
0.99

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: rs730880442; hg19: chrX-100652858; API