X-101397838-T-C

Position:

chrX-101397838-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_ModerateBP6BS2

The ENST00000218516.4(GLA):c.1261A>G(p.Met421Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000747 in 1,205,032 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000035 ( 0 hom., 2 hem., cov: 24)

Exomes 𝑓: 0.0000046 ( 0 hom. 0 hem. )

Consequence

GLA
ENST00000218516.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:2

Conservation

PhyloP100: 1.24

Variant links:

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]

GLA links:

RPL36A-HNRNPH2 (HGNC:):

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in ENST00000218516.4

BP4

Computational evidence support a benign effect (MetaRNN=0.1397458).

BP6

Variant X-101397838-T-C is Benign according to our data. Variant chrX-101397838-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 515170.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=2}.

BS2

High Hemizygotes in GnomAd4 at 2 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.1261A>G	p.Met421Val	missense_variant	7/7	ENST00000218516.4	NP_000160.1
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+2381T>C		intron_variant			NP_001186902.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.1261A>G	p.Met421Val	missense_variant	7/7	1	NM_000169.3	ENSP00000218516	P1

Frequencies

GnomAD3 genomes

AF:

0.0000355

AC:

AN:

112774

Hom.:

Cov.:

AF XY:

0.0000573

AC XY:

AN XY:

34918

show subpopulations

Gnomad AFR

AF:

0.000129

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000109

AC:

AN:

183316

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67770

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.00

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:

0.00000458

AC:

AN:

1092258

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

357870

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.00

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000355

AC:

AN:

112774

Hom.:

Cov.:

AF XY:

0.0000573

AC XY:

AN XY:

34918

show subpopulations

Gnomad4 AFR

AF:

0.000129

Gnomad4 AMR

AF:

0.00

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

Alfa

AF:

0.0000271

Hom.:

Bravo

AF:

0.0000453

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 28, 2023	In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on GLA protein function. ClinVar contains an entry for this variant (Variation ID: 515170). This variant has not been reported in the literature in individuals affected with GLA-related conditions. This variant is present in population databases (rs144060196, gnomAD 0.02%). This sequence change replaces methionine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 421 of the GLA protein (p.Met421Val). -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Nov 20, 2023	This missense variant replaces methionine with valine at codon 421 of the GLA protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Functional studies support that this variant may not have a significant impact on GLA enzyme activity (PMID: 27657681, 31036492). This variant has not been reported in individuals affected with GLA-related disorders in the literature. This variant has been identified in 4/205422 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2023

The p.M421V variant (also known as c.1261A>G), located in coding exon 7 of the GLA gene, results from an A to G substitution at nucleotide position 1261. The methionine at codon 421 is replaced by valine, an amino acid with highly similar properties. Based on data from gnomAD, the G allele has an overall frequency of 0.002% (4/205422) total alleles studied, with 2 hemizygotes observed. The highest observed frequency was 0.02% (4/19125) of African/African American alleles. In vitro studies suggest this variant may result in some reduction of enzyme activity (Benjamin ER et al. Genet Med, 2017 Apr;19:430-438; Oommen S et al. Mol Genet Metab, 2019 May;127:74-85). This amino acid position is not conserved on limited sequence alignment. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 09, 2018

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

CardioboostCm

Benign

0.097

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.34

CADD

Benign

1.2

DANN

Benign

0.74

DEOGEN2

Benign

0.13

T;.

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.32

T;T

M_CAP

Pathogenic

0.80

MetaRNN

Benign

0.14

T;T

MetaSVM

Pathogenic

2.0

MutationAssessor

Benign

0.0

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.29

PROVEAN

Benign

0.28

N;.

REVEL

Benign

0.27

Sift

Benign

0.72

T;.

Sift4G

Benign

0.33

T;.

Polyphen

0.0

B;.

Vest4

0.28

MVP

0.50

MPC

0.72

ClinPred

0.013

GERP RS

0.88

Varity_R

0.12

gMVP

0.41

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over