X-101398504-T-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 4P and 7B. PM1 PM5 BP4_Moderate BP6 BS2

The NM_000169.3(GLA):c.865A>G(p.Ile289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000331 in 1,206,911 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I289F) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., 6 hem., cov: 23)
  • Exomes 𝑓: 0.000027 (0 hom. 8 hem.)
• Consequence: GLA NM_000169.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:5 O:1
• Conservation: PhyloP100: 3.46

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:):

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• PM1: In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000169.3
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-101398504-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92568.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15808281).
• BP6: Variant X-101398504-T-C is Benign according to our data. Variant chrX-101398504-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 217400.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=4, Benign=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.865A>G	p.Ile289Val	missense_variant	6/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.300+3047T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.865A>G	p.Ile289Val	missense_variant	6/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000982 AC: 11 AN: 112019 Hom.: 0 Cov.: 23 AF XY: 0.000146 AC XY: 5 AN XY: 34191

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000380

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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

GnomAD3 exomes AF: 0.000158 AC: 29 AN: 183467 Hom.: 0 AF XY: 0.000133 AC XY: 9 AN XY: 67903

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.000948

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000274 AC: 30 AN: 1094836 Hom.: 0 Cov.: 30 AF XY: 0.0000222 AC XY: 8 AN XY: 360252

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000710

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000892 AC: 10 AN: 112075 Hom.: 0 Cov.: 23 AF XY: 0.000175 AC XY: 6 AN XY: 34257

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000680

ExAC AF: 0.000148 AC: 18

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5 Benign:5 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Fabry disease Uncertain:3 Benign:3

Uncertain significance, criteria provided, single submitter	curation	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Jan 22, 2020	The p.Ile289Val variant in GLA has been reported in 4 female individuals with unknown Fabry disease phenotype (PMID: 26415523), and has been identified in 0.096% (27/28054) of Latino chromosomes, including 9 hemizygotes, and 0.032% (6/19042) of African chromosomes, including 2 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs140329381). Please note that for diseases with clinical variability, or reduced penetrance, pathogenic variants may be present at a low frequency in the general population. This variant has also been reported in ClinVar as a VUS by GeneDx, the Laboratory for Molecular Medicine, and the Albrecht-Kossel-Institute, and as likely benign and benign by Invitae and the Swiss Institute of Bioinformatics, respectively (ID: 217400). In vitro functional studies provide some evidence that the p.Ile289Val variant may not impact protein function (PMID: 26415523). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. One additional pathogenic variant, causing a different amino acid change at the same position, p.Ile289Phe, has been reported in association with Fabry disease in the literature and ClinVar, slightly supporting that a change at this position may not be tolerated (PMID: 21598360, 10666480/Variation ID: 92568). In summary, while the clinical significance of the p.Ile289Val variant is uncertain, these data suggest that it is more likely to be benign. ACMG/AMP Criteria applied: BS1, PM5_supporting, BS3_supporting (Richards 2015). -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 23, 2023	This missense variant replaces isoleucine with valine at codon 289 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373).One study has shown this variant has little impact on GLA enzyme activity (PMID: 26415523). The same study has also shown normal lysoglobotriaosylceramide levels in a few female individuals who underwent biochemical analysis or genetic testing for Fabry Disease (PMID: 26415523). This variant has been identified in 33/205394 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The relatively high frequency of this variant in the general population suggests that this variant is unlikely to be disease-causing. However, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -
Uncertain significance, no assertion criteria provided	research	Albrecht-Kossel-Institute, Medical University Rostock	Jan 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	May 31, 2018	This variant is interpreted as a Benign, for Fabry disease, in X-linked Recessive manner. The following ACMG Tag(s) were applied: BS1 => Allele frequency is greater than expected for disorder. BS3 => Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing (PMID:26415523). -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Dec 29, 2023	- -

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 14, 2018	This variant is associated with the following publications: (PMID: 26415523, 27916943) -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Sep 25, 2019	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 24, 2017

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: This variant has been seen in one patient with Fabry disease. It is present in ExAC with a Max MAF of 0.11% in Latino chrs (with 2 hemizygotes). It's been seen in 1 female with symptoms of Fabry disease. It is classified in ClinVar with 1 star as VUS by GeneDx and Albrecht-Kossel-Institute,Medical University Rostock. -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2020

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Migalastat response Other:1

drug response, no assertion criteria provided

research

Albrecht-Kossel-Institute, Medical University Rostock

Jan 01, 2014

- Pharmacological Chaperone response: yes

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
CardioboostCm	Uncertain	0.18
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	20
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.77	D;.
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.82	T;T
M_CAP	Pathogenic	0.58	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.2	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.85	N;.
REVEL	Uncertain	0.62
Sift	Benign	0.23	T;.
Sift4G	Benign	0.18	T;.
Polyphen		0.97	D;.
Vest4		0.76
MVP		0.87
MPC		0.60
ClinPred		0.13	T
GERP RS		4.7
Varity_R		0.46
gMVP		0.94

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

LitVar

Other links and lift over

dbSNP: rs140329381; hg19: chrX-100653492;