X-101407897-G-C

Position:

• chrX-101407897-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000169.3(GLA):​c.7C>G​(p.Leu3Val) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance,drug response (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L3P) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Uncertain significance; drug response no assertion criteria provided U:1 O:1
• Conservation: PhyloP100: -0.163

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 Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a signal_peptide (size 30) in uniprot entity AGAL_HUMAN there are 11 pathogenic changes around while only 4 benign (73%) in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.7C>G	p.Leu3Val	missense_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4039G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.7C>G	p.Leu3Val	missense_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance; drug response

Submissions summary: Uncertain:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Fabry disease Uncertain:1

Uncertain significance, 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: yes

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
CardioboostCm	Uncertain	0.30
BayesDel_addAF	Benign	-0.013	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.19	T;.
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.52	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Pathogenic	2.0	D
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.30	N;.
REVEL	Benign	0.17
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.027	D;.
Polyphen		0.0050	B;.
Vest4		0.71
MutPred		0.23		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.77
MPC		1.8
ClinPred		0.80	D
GERP RS		1.0
Varity_R		0.16
gMVP		0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.24		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs869312133; hg19: chrX-100662885;