NM_000169.3:c.1072_1074delGAG

Variant names:

• chrX-101398024-TCTC-T
• rs730880453
• NM_000169.3:c.1072_1074delGAG

Variant summary

Our verdict is Pathogenic. The variant received 17 ACMG points: 17P and 0B. PS3 PM1 PM2 PM4_Supporting PP5_Very_Strong

The NM_000169.3(GLA):​c.1072_1074delGAG​(p.Glu358del) variant causes a conservative inframe deletion change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000207834: Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID:27657681)" and additional evidence is available in ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 conservative_inframe_deletion
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:8
• Conservation: PhyloP100: 7.37
• Publications: 20 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 17 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000207834: Published functional studies found this variant is associated with significantly reduced enzyme activity (PMID: 27657681);; SCV001361588: significantly reduced GLA activity in both patient derived samples and in in vitro studies, furthermore the enzyme activity was shown to be non-responsive to 1-deoxygalactonojirimycin (DGJ) treatment (Shin_2008).; SCV006335663: At least one functional study has demonstrated a substantial alteration in protein function relative to the wild-type. PMID:27657681
• PM1: In a hotspot region, there are 24 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 13 uncertain in NM_000169.3
• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in NM_000169.3. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant X-101398024-TCTC-T is Pathogenic according to our data. Variant chrX-101398024-TCTC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 180844.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.1072_1074delGAG	p.Glu358del	conservative_inframe_deletion	Exon 7 of 7	NP_000160.1	P06280
	GLA	NM_001406747.1		c.1195_1197delGAG	p.Glu399del	conservative_inframe_deletion	Exon 8 of 8	NP_001393676.1	A0A3B3IUC4
	RPL36A-HNRNPH2	NM_001199973.2		c.300+2570_300+2572delCCT		intron	N/A	NP_001186902.2	H7BZ11

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLA	ENST00000218516.4	TSL:1 MANE Select	c.1072_1074delGAG	p.Glu358del	conservative_inframe_deletion	Exon 7 of 7	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+2570_300+2572delCCT		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.1195_1197delGAG	p.Glu399del	conservative_inframe_deletion	Exon 8 of 8	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes Cov.: 23

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
5	-	-	Fabry disease (5)
3	-	-	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.4
Mutation Taster		=31/69	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs730880453; hg19: chrX-100653012;