rs869312144

Positions:

• chrX-101401689-C-A
• chrX-101401689-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000169.3(GLA):​c.490G>T​(p.Val164Leu) 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V164I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2 B:1 O:1
• Conservation: PhyloP100: 4.99

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:):

ACMG classification

Verdict is Pathogenic. Variant got 10 ACMG points.

• PM1: In a hotspot region, there are 9 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.490G>T	p.Val164Leu	missense_variant	3/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+6232C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.490G>T	p.Val164Leu	missense_variant	3/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2 Benign:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Uncertain:2 Benign:1

Benign, no assertion criteria provided	clinical testing	Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital	Jul 03, 2017	Extensive evaluation of family with this variant. All investigations completely normal, including renal biopsy (with no Gb3 depositys) -
Uncertain significance, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: no

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
CardioboostCm	Uncertain	0.72
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.68
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.97	D;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.98	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Pathogenic	3.7	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.88
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.81	P;.
Vest4		0.93
MutPred		0.73		Loss of methylation at K168 (P = 0.1018);.;
MVP		1.0
MPC		0.86
ClinPred		0.99	D
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

Other links and lift over

dbSNP: rs869312144; hg19: chrX-100656677; COSMIC: COSV54509475; COSMIC: COSV54509475;