rs28935488

Positions:

• chrX-101398563-A-C
• chrX-101398563-A-G
• chrX-101398563-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000169.3(GLA):​c.806T>G​(p.Val269Gly) 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).

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic; drug response no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 9.32

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]

GLA (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.967
• PP5: Variant X-101398563-A-C is Pathogenic according to our data. Variant chrX-101398563-A-C is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 217399.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.806T>G	p.Val269Gly	missense_variant	6/7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.806T>G	p.Val269Gly	missense_variant	6/7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3106A>C		intron_variant		4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic; drug response

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Fabry disease Pathogenic:1

Pathogenic, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- -

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	Uncertain	0.55
CardioboostCm	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.71	D
BayesDel_noAF	Pathogenic	0.79
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.98	D;.
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	D;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.97	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.2	M;.
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-6.8	D;.
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		1.0	D;.
Vest4		0.87
MutPred		0.78		Loss of stability (P = 0.0166);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs28935488; hg19: chrX-100653551;