X-101403933-C-T

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_000169.3(GLA):c.247G>A(p.Asp83Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000373 in 1,207,559 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000040 ( 0 hom. 12 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:10B:1

Conservation

PhyloP100: 3.38

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: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]

RPL36A-HNRNPH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 12 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.247G>A	p.Asp83Asn	missense_variant	Exon 2 of 7	ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 link	c.247G>A	p.Asp83Asn	missense_variant	Exon 2 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.301-8003C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.00000888

AC:

AN:

112649

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34795

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000187

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000218

AC:

AN:

183388

Hom.:

AF XY:

0.00

AC XY:

AN XY:

67824

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000489

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000402

AC:

AN:

1094910

Hom.:

Cov.:

AF XY:

0.0000333

AC XY:

AN XY:

360392

show subpopulations

Gnomad4 AFR exome

AF:

0.0000380

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:

0.0000512

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000888

AC:

AN:

112649

Hom.:

Cov.:

AF XY:

0.0000287

AC XY:

AN XY:

34795

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000187

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000868

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:10Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Uncertain:6

Uncertain significance, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2023	This missense variant replaces aspartic acid with asparagine at codon 83 of the GLA protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function. A functional study has shown that this variant results in slightly reduced GLA enzyme activity (PMID: 27657681). This variant has been reported in two female affected with heart diseases (PMID: 24496231, 29227985), two individuals affected with stroke (PMID: 23306324, 23935525, 26070511), and in one female affected with kidney disease (PMID: 24365053). GLA enzyme activity or Gb3 levels were reported to be normal in some of these patients (PMID: 24496231, 26070511, 29227985), as well as abnormal in a few others (PMID: 23306324, 24365053). This variant has also been reported in hemizygous state in one patient's brother, who showed no manifestations of Fabry disease, and had normal plasma and leukocyte GAL enzyme activities (PMID: 26070511). This variant has been identified in 4/183388 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 26, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 83 of the GLA protein (p.Asp83Asn). This variant is present in population databases (rs782722577, gnomAD 0.005%). This missense change has been observed in individual(s) with reduced alpha-galactosidase activity on screening tests and/or individuals affected with stroke (PMID: 23306324, 23935525, 24365053, 26070511). ClinVar contains an entry for this variant (Variation ID: 222202). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt GLA protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on GLA function (PMID: 27657681). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 13, 2023	This missense variant replaces aspartic acid with asparagine at codon 83 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). A functional study has shown that this variant results in slightly reduced GLA enzyme activity (PMID: 27657681). This variant has been reported in two individuals affected with heart diseases (PMID: 24496231, 29227985), two individuals affected with stroke (PMID: 23306324, 23935525, 26070511), and in one female affected with kidney disease (PMID: 24365053). GLA enzyme activity or Gb3 levels were reported to be normal in some of these patients (PMID: 24496231, 26070511, 29227985), as well as abnormal in a few others (PMID: 23306324, 24365053). This variant has also been reported in hemizygous state in one patient's brother, who showed no manifestations of Fabry disease, and had normal plasma and leukocyte GAL enzyme activities (PMID: 26070511). This variant has been identified in 4/183388 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided

Uncertain:3Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 14, 2016	- -
Uncertain significance, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2019	See Variant Classification Assertion Criteria. -
Uncertain significance, no assertion criteria provided	provider interpretation	Stanford Center for Inherited Cardiovascular Disease, Stanford University	Sep 22, 2017	- -

Cardiovascular phenotype

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2022

The p.D83N variant (also known as c.247G>A), located in coding exon 2 of the GLA gene, results from a G to A substitution at nucleotide position 247. The aspartic acid at codon 83 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been identified in cohorts of subjects with stroke, heart disease and kidney disease (Lukas J et al. PLoS Genet., 2013 Aug;9:e1003632; Herrera J et al. Clin. Nephrol., 2014 Feb;81:112-20; Ferreira S et al. Clin. Chim. Acta, 2015 Jul;447:96-104; Schiffmann R et al. Genet. Med., 2018 07;20:754-759). One female subject with stroke was noted to carry this alteration, but the alteration was also noted in her unaffected brother (Ferreira S et al. Clin. Chim. Acta, 2015 Jul;447:96-104). Based on data from gnomAD, the A allele has an overall frequency of 0.0022% (4/183388) total alleles studied, with 0 hemizygote(s) observed. The highest observed frequency was 0.0049% (4/81872) of European (non-Finnish) alleles. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

CardioboostCm

Uncertain

0.65

BayesDel_addAF

Benign

-0.042

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

D;.

FATHMM_MKL

Uncertain

0.97

LIST_S2

Pathogenic

0.99

D;D

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Pathogenic

0.87

MutationAssessor

Uncertain

2.4

M;.

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.4

N;.

REVEL

Uncertain

0.64

Sift

Uncertain

0.018

D;.

Sift4G

Uncertain

0.018

D;.

Polyphen

0.98

D;.

Vest4

0.20

MVP

0.99

MPC

0.79

ClinPred

0.34

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.84

gMVP

0.92

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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