X-101407842-A-G

Position:

• chrX-101407842-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_000169.3(GLA):​c.62T>C​(p.Leu21Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000892 in 112,146 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L21F) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2 O:1
• Conservation: PhyloP100: 3.13

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 8 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 9 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• PP5: Variant X-101407842-A-G is Pathogenic according to our data. Variant chrX-101407842-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 217374.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.62T>C	p.Leu21Pro	missense_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4094A>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.62T>C	p.Leu21Pro	missense_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.00000892 AC: 1 AN: 112146 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34306

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000188

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000892 AC: 1 AN: 112146 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34306

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000188

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Invitae	Apr 01, 2019	This sequence change replaces leucine with proline at codon 21 of the GLA protein (p.Leu21Pro). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and proline. This variant is not present in population databases (ExAC no frequency). For these reasons, this allele has been classified as Likely Pathogenic. This variant has been reported to affect GLA protein function (PMID: 26415523). This variant has been observed in individuals affected with GLA-related conditions (PMID: 26415523, 30038331, Invitae). ClinVar contains an entry for this variant (Variation ID: 217374). -
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	Benign	0.10
CardioboostCm	Uncertain	0.19
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.34
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Uncertain	0.68	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.56	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.2	D
MutationAssessor	Benign	1.9	L;.
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.3	N;.
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0070	D;.
Sift4G	Uncertain	0.022	D;.
Polyphen		0.97	D;.
Vest4		0.97
MutPred		0.82		Loss of helix (P = 0.0041);Loss of helix (P = 0.0041);
MVP		1.0
MPC		1.9
ClinPred		0.82	D
GERP RS		5.4
Varity_R		0.71
gMVP		0.96

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: rs869312135; hg19: chrX-100662830;