rs869312144

Variant names:

• chrX-101401689-C-A
• rs869312144
• NM_000169.3:c.490G>T

Your query was ambiguous. Multiple possible variants found:

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

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. 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. V164G) has been classified as Likely pathogenic.

• 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: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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 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, 0.943

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.490G>T	p.Val164Leu	missense_variant	Exon 3 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.490G>T	p.Val164Leu	missense_variant	Exon 3 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+6232C>A		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

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

Jul 03, 2017

Center for Medical Genetics and Molecular Medicine, Haukeland University Hospital

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Extensive evaluation of family with this variant. All investigations completely normal, including renal biopsy (with no Gb3 depositys) -

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

- -

Jul 15, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Migalastat response Other:1

Jan 01, 2014

Albrecht-Kossel-Institute, Medical University Rostock

Significance: drug response

Review Status: no assertion criteria provided

Collection Method: research

- 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;.
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;