rs104894849

Variant names:

• chrX-101398004-A-C
• NM_000169.3:c.1095T>G

Your query was ambiguous. Multiple possible variants found:

• chrX-101398004-A-C
• chrX-101398004-A-G
• chrX-101398004-A-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_000169.3(GLA):​c.1095T>G​(p.Tyr365*) variant causes a stop gained change involving the alteration of a non-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 Pathogenic (★★).

• Frequency: Genomes: not found (cov: 24)
• Consequence: GLA NM_000169.3 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 0.0510

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

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-101398004-A-C is Pathogenic according to our data. Variant chrX-101398004-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2635243.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3	c.1095T>G	p.Tyr365*	stop_gained	Exon 7 of 7	ENST00000218516.4	NP_000160.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4	c.1095T>G	p.Tyr365*	stop_gained	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4
RPL36A-HNRNPH2	ENST00000409170.3	c.300+2547A>C		intron_variant	Intron 4 of 4	4		ENSP00000386655.4

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GLA-related disorder Pathogenic:1

Nov 09, 2022

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The GLA c.1095T>G variant is predicted to result in premature protein termination (p.Tyr365*). This variant was reported in an individual with Fabry disease (Sakuraba et al 2018. PubMed ID: 30386727). Another DNA variant leading to the same protein truncation (c.1095T>A, p.Tyr365*) was reported in a family with Fabry disease (Miyamura et al. 1996. PubMed ID: 8878432). In a heterozygote individual in this family, lymphocyte alpha-Gal A activity was approximately 30% of the normal control and severe clinical symptoms were apparent. Functional studies support pathogenicity and suggest a dominant negative effect and the importance of the C terminus for protein activity (Miyamura et al. 1996. PubMed ID: 8878432). Although this variant occurs in the last exon and may not succumb to the nonsense mediated decay, it is shortening the protein product by 65 amino acid residues and many pathogenic GLA mutations are reported downstream of this variant. This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Nonsense variants in GLA gene are expected to be pathogenic. This variant is interpreted as pathogenic. -

Cardiovascular phenotype Pathogenic:1

Aug 19, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Y365* pathogenic mutation (also known as c.1095T>G), located in coding exon 7 of the GLA gene, results from a T to G substitution at nucleotide position 1095. This changes the amino acid from a tyrosine to a stop codon within coding exon 7. This alteration occurs at the 3' terminus of theGLA gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 15% of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant has been detected in individuals with features consistent with Fabry disease, including a hemizygous male reported to have classic Fabry disease; however, details were limited (Sakuraba H et al. Mol Genet Metab Rep, 2018 Dec;17:73-79; Kobayashi M et al. J Hum Genet, 2019 Jul;64:695-699; Nakano S et al. PLoS One, 2015 Jun;10:e0128351). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	22
DANN	Benign	0.92
FATHMM_MKL	Benign	0.19	N
Vest4		0.85
GERP RS		-10
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-100652992;