chrX-101403906-C-A

Variant names:

• chrX-101403906-C-A
• rs886041315
• NM_000169.3:c.274G>T

Variant summary

Our verdict is Pathogenic. The variant received 23 ACMG points: 23P and 0B. PS3 PM1 PM2 PM5 PP2 PP3_Strong PP5_Very_Strong

The NM_000169.3(GLA):​c.274G>T​(p.Asp92Tyr) 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 Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000329699: Functional analysis of D92Y found that it is associated with no detectable residual enzyme activity (Wu et al., 2011)." and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D92V) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.90
• Publications: 8 publications found

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:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

ACMG classification

Our verdict: Pathogenic. The variant received 23 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000329699: Functional analysis of D92Y found that it is associated with no detectable residual enzyme activity (Wu et al., 2011).; SCV001338551: At least one publication reports experimental evidence evaluating an impact on protein function (example, Wu_2011) while at-least two publications report in-silico computational evidence supporting a damaging impact on protein function (example, Saito_2013, Riera_2015). The most pronounced variant effect results in <10% of normal enzyme activity (Wu_2011).; SCV006335946: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type (PMID:21598360;27657681).
• PM1: In a hotspot region, there are 38 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-101403905-T-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 3724333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 218 curated pathogenic missense variants (we use a threshold of 10). The gene has 17 curated benign missense variants. Gene score misZ: 1.8759 (below the threshold of 3.09). Trascript score misZ: NaN (below the threshold of 3.09). GenCC associations: The gene is linked to Fabry disease.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.995
• PP5: Variant X-101403906-C-A is Pathogenic according to our data. Variant chrX-101403906-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280003.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000169.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	NM_000169.3	MANE Select	c.274G>T	p.Asp92Tyr	missense	Exon 2 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.397G>T	p.Asp133Tyr	missense	Exon 3 of 8	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.274G>T	p.Asp92Tyr	missense	Exon 2 of 6	NP_001393677.1	A0A6Q8PHD1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.274G>T	p.Asp92Tyr	missense	Exon 2 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.301-8030C>A		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.397G>T	p.Asp133Tyr	missense	Exon 3 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Fabry disease (3)
2	-	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
CardioboostCm	Pathogenic	0.97
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	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.96	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Pathogenic	4.7	H
PhyloP100		7.9
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-8.5	D
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.97		Loss of phosphorylation at Y88 (P = 0.1288)
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		5.8
Varity_R		0.99
gMVP		1.0
Mutation Taster		=2/98	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs886041315; hg19: chrX-100658894;