rs28935489

Positions:

• chrX-101398479-G-A
• chrX-101398479-G-C
• chrX-101398479-G-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The ENST00000218516.4(GLA):​c.890C>T​(p.Ser297Phe) 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S297Y) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA ENST00000218516.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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 Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in ENST00000218516.4
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398480-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 839647.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992
• PP5: Variant X-101398479-G-A is Pathogenic according to our data. Variant chrX-101398479-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 10737.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-101398479-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3	c.890C>T	p.Ser297Phe	missense_variant	6/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2	c.300+3022G>A		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.890C>T	p.Ser297Phe	missense_variant	6/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jun 10, 2022	For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Ser297 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7504405, 12428061, 19287194, 26238931). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 10737). This missense change has been observed in individual(s) with Fabry disease (PMID: 7504405, 19287194, 31620600). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 297 of the GLA protein (p.Ser297Phe). -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 01, 1993	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
CardioboostCm	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	1.0	D;.
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.
MutationTaster	Benign	1.0	A
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		1.0
MutPred		0.97		Loss of disorder (P = 0.0759);.;
MVP		1.0
MPC		1.8
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.99
gMVP		1.0

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: rs28935489; hg19: chrX-100653467;