X-101398389-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PM5PP3_ModeratePP5

The NM_000169.3(GLA):​c.980A>T​(p.Gln327Leu) 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 Pathogenic,drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q327K) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 23)

Consequence

GLA
NM_000169.3 missense

Scores

12
4
2

Clinical Significance

Pathogenic; drug response no assertion criteria provided P:1O:1

Conservation

PhyloP100: 8.02
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PM1
In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000169.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chrX-101398390-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 10739.Status of the report is no_assertion_criteria_provided, 0 stars.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.877
PP5
Variant X-101398389-T-A is Pathogenic according to our data. Variant chrX-101398389-T-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 217408.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
GLANM_000169.3 linkuse as main transcriptc.980A>T p.Gln327Leu missense_variant 6/7 ENST00000218516.4
RPL36A-HNRNPH2NM_001199973.2 linkuse as main transcriptc.300+2932T>A intron_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
GLAENST00000218516.4 linkuse as main transcriptc.980A>T p.Gln327Leu missense_variant 6/71 NM_000169.3 P1

Frequencies

GnomAD3 genomes
Cov.:
23
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic; drug response
Submissions summary: Pathogenic:1Other:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

Fabry disease Pathogenic:1
Pathogenic, no assertion criteria providedresearchAlbrecht-Kossel-Institute, Medical University RostockJan 01, 2014- -
Migalastat response Other:1
drug response, no assertion criteria providedresearchAlbrecht-Kossel-Institute, Medical University RostockJan 01, 2014- Pharmacological Chaperone response: yes

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.59
CardioboostCm
Pathogenic
0.97
BayesDel_addAF
Pathogenic
0.50
D
BayesDel_noAF
Pathogenic
0.48
CADD
Uncertain
26
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.99
D;.
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D
M_CAP
Pathogenic
0.98
D
MetaRNN
Pathogenic
0.88
D;D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Pathogenic
4.4
H;.
MutationTaster
Benign
1.0
D
PrimateAI
Uncertain
0.55
T
PROVEAN
Pathogenic
-4.6
D;.
REVEL
Pathogenic
0.88
Sift
Uncertain
0.017
D;.
Sift4G
Benign
0.066
T;.
Polyphen
1.0
D;.
Vest4
0.96
MutPred
0.60
Loss of disorder (P = 0.0339);.;
MVP
1.0
MPC
1.7
ClinPred
1.0
D
GERP RS
5.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.97
gMVP
0.98

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: rs869312160; hg19: chrX-100653377; API