rs869312139

Positions:

• chrX-101407714-T-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3 PP5

The NM_000169.3(GLA):​c.190A>T​(p.Ile64Phe) variant causes a missense change involving the alteration of a non-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: 0.675

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a disulfide_bond (size 42) in uniprot entity AGAL_HUMAN there are 10 pathogenic changes around while only 0 benign (100%) in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75
• PP5: Variant X-101407714-T-A is Pathogenic according to our data. Variant chrX-101407714-T-A is described in ClinVar as [Pathogenic, drug_response]. Clinvar id is 217378.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.190A>T	p.Ile64Phe	missense_variant	1/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.301-4222T>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.190A>T	p.Ile64Phe	missense_variant	1/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

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	0.46
CardioboostCm	Uncertain	0.37
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.93	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;T
M_CAP	Pathogenic	0.93	D
MetaRNN	Uncertain	0.74	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.5	D;.
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;.
Polyphen		0.99	D;.
Vest4		0.74
MutPred		0.57		Gain of ubiquitination at K67 (P = 0.1184);Gain of ubiquitination at K67 (P = 0.1184);
MVP		0.96
MPC		1.3
ClinPred		0.98	D
GERP RS		0.39
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: rs869312139; hg19: chrX-100662702;