rs104894848

Positions:

• chrX-101407710-C-G

Variant summary

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

The ENST00000218516.4(GLA):​c.194G>C​(p.Ser65Thr) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S65G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA ENST00000218516.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 5.92

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 hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in ENST00000218516.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751
• PP5: Variant X-101407710-C-G is Pathogenic according to our data. Variant chrX-101407710-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 10766.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chrX-101407710-C-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.194G>C	p.Ser65Thr	missense_variant, splice_region_variant	1/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.301-4226C>G		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.194G>C	p.Ser65Thr	missense_variant, splice_region_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

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Fabry disease Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
CardioboostCm	Uncertain	0.46
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Pathogenic	37
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.75	D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;.
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D;.
Sift4G	Uncertain	0.0060	D;.
Polyphen		0.99	D;.
Vest4		0.54
MutPred		0.54		Gain of catalytic residue at S65 (P = 0.0129);Gain of catalytic residue at S65 (P = 0.0129);
MVP		0.94
MPC		1.6
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.96
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.92		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.92		Position offset: -14
DS_DL_spliceai		0.68		Position offset: 0

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

Publications

LitVar

Other links and lift over

dbSNP: rs104894848; hg19: chrX-100662698;