chrX-101399747-C-T

Variant names:

• chrX-101399747-C-T
• rs199473684
• NM_000169.3:c.640-801G>A

Variant summary

Our verdict is Pathogenic. The variant received 13 ACMG points: 14P and 1B. PS3 PM2 PP5_Very_Strong BS1_Supporting

The NM_000169.3(GLA):​c.640-801G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000178 in 112,274 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000748692: Studies have shown that this variant results in insertion of 57bp pseudoexon sequence in intron 4, and produces a non-functional protein and/or introduces a premature termination codon (PMID:11828341, 27595546, 28430823)." and additional evidence is available in ClinVar.

• Frequency: Genomes: 𝑓 0.000018 (0 hom., 1 hem., cov: 23)
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:18 U:1 O:1
• Conservation: PhyloP100: 0.201
• Publications: 5 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 13 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV000748692: Studies have shown that this variant results in insertion of 57bp pseudoexon sequence in intron 4, and produces a non-functional protein and/or introduces a premature termination codon (PMID: 11828341, 27595546, 28430823).; SCV001422791: RNAseq analysis performed on affected tissues shows that the c.639+919G>A variant creates alternative splicing in the majority of transcripts, leading to an in-frame cryptic exon that includes a stop codon and results in a truncated or absent protein.; SCV001734431: RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823, 37254000).; SCV002014858: Several in vitro studies demonstrated, that the variant activates a cryptic exon between exon 4 and 5 that results in the insertion of 57 intronic nucleotide, leading to a premature stop codon (Ishii 2002, Chiang 2017, Chang 2017). Though the truncated variant-protein had no enzyme activity (Ishii 2002), since the normal transcript was also present, it resulted in some residual enzyme activity in samples from male individuals carrying the variant (Ishii 2002, Lin 2010, Chien 2012, Chang 2017).; SCV004839054: RNA studies have shown that this variant causes the inclusion of 57 bases from intron 4 as a pseudoexon, resulting in the expression of truncated protein (PMID: 11828341, 27595546, 28430823, 37254000).; SCV005418482: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006335582: At least one splicing study identified that this variant results in aberrant splicing (PMID:11828341;37254000).; SCV006585695: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 11828341, 28430823, 37833114).; SCV001788703: "In vitro functional studies have shown that c.640-801 G>A creates a cryptic splice site that causes abnormal gene splicing through introduction of an additional 57 nucleotides into the GLA transcript (PMID: 27595546, 11828341, 28430823); Additional functional studies have shown that this variant is associated with approximately 10% residual alpha-galactosidase activity in patient lymphoblasts (PMID: 11828341);"; SCV000203980: Functional studies have shown that the c.639+919G>A variant results in the accumulation of lamellar bodies and glycosphingolipids in induced pluripotent stem cell cardiomyocytes from a patient with Fabry disease (Chou 2017).; SCV002658884: "In a study of patient-derived induced pluripotent stem cells, cardiomyocytes with this alteration recapitulated the abnormal cardiac phenotype (Chou SJ et al. Int J Cardiol. 2017;232:255-263)."; SCV005348755: Functional studies support its pathogenicity (see, for example, Lin et al. 2010. PubMed ID: 20821055; Chien et al. 2012. PubMed ID: 22437327; Hsu et al. 2014. PubMed ID: 24980630).
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101399747-C-T is Pathogenic according to our data. Variant chrX-101399747-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 10768.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000178 (2/112274) while in subpopulation EAS AF = 0.000556 (2/3599). AF 95% confidence interval is 0.0000979. There are 0 homozygotes in GnomAd4. There are 1 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.640-801G>A		intron	N/A	NP_000160.1	P06280
	GLA	NM_001406747.1		c.763-801G>A		intron	N/A	NP_001393676.1	A0A3B3IUC4
	GLA	NM_001406748.1		c.640-801G>A		intron	N/A	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.640-801G>A		intron	N/A	ENSP00000218516.4	P06280
	RPL36A-HNRNPH2	ENST00000409170.3	TSL:4	c.300+4290C>T		intron	N/A	ENSP00000386655.4	H7BZ11
	GLA	ENST00000649178.1		c.763-801G>A		intron	N/A	ENSP00000498186.1	A0A3B3IUC4

Frequencies

GnomAD3 genomes AF: 0.0000178 AC: 2 AN: 112222 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000554

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.0000178 AC: 2 AN: 112274 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34448

African (AFR) AF: 0.00 AC: 0 AN: 30944

American (AMR) AF: 0.00 AC: 0 AN: 10566

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2654

East Asian (EAS) AF: 0.000556 AC: 2 AN: 3599

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6070

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53278

Other (OTH) AF: 0.00 AC: 0 AN: 1535

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
10	-	-	Fabry disease (11)
4	-	-	not provided (4)
1	-	-	Cardiomyopathy (1)
1	-	-	Cardiovascular phenotype (1)
-	1	-	Fabry disease, cardiac variant (1)
1	-	-	Fabry disease;C0007194:Hypertrophic cardiomyopathy (1)
1	-	-	GLA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	16
DANN	Benign	0.62
PhyloP100		0.20
Mutation Taster		=99/1	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		3.0
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: -3

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

Other links and lift over

dbSNP: rs199473684; hg19: chrX-100654735;