rs727504773

Variant names:

• chrX-101398565-TAACTG-AAAGTTGCC
• rs727504773
• NM_000169.3:c.802-3_804delCAGTTAinsGGCAACTTT

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1_Strong PM2 PP2 PP5_Moderate

The NM_000169.3(GLA):​c.802-3_804delCAGTTAinsGGCAACTTT​(p.Leu268delinsAsnPhe) variant causes a splice acceptor, missense, splice region, intron 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L268F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 23)
• Consequence: GLA NM_000169.3 splice_acceptor, missense, splice_region, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.32
• Publications: 0 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: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.15348837 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.8, offset of 26, new splice context is: attggcaactttggcctcAGctg. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• 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.
• PP5: Variant X-101398565-TAACTG-AAAGTTGCC is Pathogenic according to our data. Variant chrX-101398565-TAACTG-AAAGTTGCC is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179299.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.802-3_804delCAGTTAinsGGCAACTTT	p.Leu268delinsAsnPhe	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.802-3_804delCAGTTAinsGGCAACTTT	p.Leu268delinsAsnPhe	splice_acceptor_variant, missense_variant, splice_region_variant, intron_variant		1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+3108_300+3113delTAACTGinsAAAGTTGCC		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

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

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Fabry disease Pathogenic:1

Sep 19, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The 802-3_804delinsGGCAACTTT variant in GLA has not been previously reported in individuals with cardiomyopathy or Fabry disease. Data from large population stu dies is insufficient to assess the frequency of this variant. This variant is lo cated in a 3' splice region and alters the invariant region (+/- 1,2) of the spl ice consensus. This is predicted to cause altered splicing leading to an abnorma l or absent protein. Variants in GLA are strongly associated with Fabry disease , an X-linked lysosomal storage disorder, which may present as isolated HCM (Bee r 2002). In summary, this variant is likely to be pathogenic, but additional stu dies are needed to fully establish its clinical significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

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

Other links and lift over

dbSNP: rs727504773; hg19: chrX-100653553;