rs869312344

chrX-101400700-C-GchrX-101400700-C-T

Variant summary

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

The NM_000169.3(GLA):c.605G>C(p.Cys202Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000928 in 1,077,491 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples 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. C202R) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.3e-7 (0 hom. 0 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.89

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 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101400700-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222314.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-101400700-C-G is Pathogenic according to our data. Variant chrX-101400700-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1466492.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.605G>C	p.Cys202Ser	missense_variant	4/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+5243C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.605G>C	p.Cys202Ser	missense_variant	4/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000551 AC: 1 AN: 181578 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66136

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000723

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.28e-7 AC: 1 AN: 1077491 Hom.: 0 Cov.: 25 AF XY: 0.00 AC XY: 0 AN XY: 345625

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000332

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Aug 27, 2022

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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: 1466492). This missense change has been observed in individual(s) with Fabry disease (Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 202 of the GLA protein (p.Cys202Ser). This variant disrupts the p.Cys202 amino acid residue in GLA. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9100224, 19387866, 23935525; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
CardioboostCm	Uncertain	0.77
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.79
Cadd	Pathogenic	27
Dann	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D;D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-9.9	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.83
MutPred		0.91		Loss of sheet (P = 0.0357);.;
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs869312344; hg19: chrX-100655688;