X-101397997-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 3P and 13B. PM1PP2BP4_StrongBP6BS1BS2

The NM_000169.3(GLA):c.1102G>A(p.Ala368Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000488 in 1,208,524 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 15 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. A368P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., 8 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 7 hem. )

Consequence

GLA
NM_000169.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:6

Conservation

PhyloP100: -0.928

Publications

15 publications found

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 was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

PM1

In a hotspot region, there are 21 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000169.3

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.03427121).

BP6

Variant X-101397997-C-T is Benign according to our data. Variant chrX-101397997-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 42451.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000295 (33/111981) while in subpopulation AFR AF = 0.00107 (33/30821). AF 95% confidence interval is 0.000784. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 8 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.1102G>A	p.Ala368Thr	missense_variant	Exon 7 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.1102G>A	p.Ala368Thr	missense_variant	Exon 7 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+2540C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.000295

AC:

AN:

111925

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00107

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

GnomAD2 exomes

AF:

0.0000654

AC:

AN:

183423

AF XY:

0.0000589

show subpopulations

Gnomad AFR exome

AF:

0.000912

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

0.0000237

AC:

AN:

1096543

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

361935

show subpopulations

African (AFR)

AF:

0.000910

AC:

AN:

26360

American (AMR)

AF:

0.00

AC:

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19378

East Asian (EAS)

AF:

0.00

AC:

AN:

30202

South Asian (SAS)

AF:

0.00

AC:

AN:

54108

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40532

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4123

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840603

Other (OTH)

AF:

0.0000434

AC:

AN:

46031

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000295

AC:

AN:

111981

Hom.:

Cov.:

AF XY:

0.000234

AC XY:

AN XY:

34181

show subpopulations

African (AFR)

AF:

0.00107

AC:

AN:

30821

American (AMR)

AF:

0.00

AC:

AN:

10558

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3554

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6047

Middle Eastern (MID)

AF:

0.00

AC:

AN:

219

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53209

Other (OTH)

AF:

0.00

AC:

AN:

1510

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000186

Hom.:

Bravo

AF:

0.000302

ESP6500AA

AF:

0.000522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000988

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Benign:4

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

The p.Ala368Thr variant in GLA has been reported in 1 African American female with Fabry Disease (PMID: 24503780), and has been identified in 0.1% (19/18974) of African chromosomes, including 8 hemizygotes, by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144994244). This variant has also been reported in ClinVar as a VUS by Invitae and the Laboratory for Molecular Medicine (Partners Healthcare) and likely benign by GeneDx (Variation ID:42451). In vitro functional studies provide some evidence that the p.Ala368Thr variant may not impact protein function (PMID: 23935525, 24334114, 27576502). However, these types of assays may not accurately represent biological function. Computational prediction tools, including splice predictors, and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. One affected individual with this variant has an alternative molecular basis for Fabry disease, suggesting this variant may not cause the disease (PMID: 24503780). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: BS1, BP4, BS3_supporting, BP5 (Richards 2015). -

May 22, 2024

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Uncertain:2Benign:1

Apr 08, 2015

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Jul 06, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant classified as Uncertain Significance - Favor Benign. The Ala368Thr varia nt in GLA has been identified in 2/3835 African American chromosomes from a broa d population by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu /EVS). Alanine (Ala) at position 368 is not conserved in mammals with other spec ies carrying various other amino acid residues and 1 species (atlantic salmon) c arries a threonine (Thr; this variant), suggesting that this change may be toler ated. In addition, computational analyses (biochemical amino acid properties, Al ignGVGD, PolyPhen2, and SIFT) suggest that this variant may not impact the prote in, though this information is not predictive enough to rule out pathogenicity. In summary, the frequency of this variant and lack of amino acid conservation su ggests that it may be more likely benign, but additional information is needed t o fully assess its clinical significance. -

Jan 29, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: GLA c.1102G>A (p.Ala368Thr) results in a non-conservative amino acid change located in the Alpha galactosidase A, C-terminal beta-sandwich domain (IPR035373) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.9e-05 in 1208524 control chromosomes, including 15 hemizygotes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in GLA causing Fabry Disease (4.9e-05 vs 0.005), allowing no conclusion about variant significance. c.1102G>A has been reported in the literature in male and female individuals suspected or affected with Fabry Disease (e.g. Turaca_2012, Lukas_2013, Pereira_2014, Silva_2016, Stiles_2020, Varela_2020) and an individual affected with dilated cardiomyopathy (Pugh_2014). One of the reported male patients was a 73-year-old undergoing hemodialysis for approximately 5 years who denied experiencing classical FD symptoms; clinical manifestations of the patient included: Cornea verticillata, Fabry nephropathy and Left ventricular hypertrophy (Silva_2016). These reports do not provide unequivocal conclusions about association of the variant with Fabry Disease. Multiple publications report experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in >50%-90% of normal enzyme activity (e.g. Lukas_2013, Benjamin_2017, Oommen_2019). The following publications have been ascertained in the context of this evaluation (PMID: 27657681, 29330335, 37441486, 23935525, 30985853, 31036492, 24334114, 24503780, 27576502, 32418857, 22551898, 31996269). ClinVar contains an entry for this variant (Variation ID: 42451). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided

Uncertain:1

Jul 08, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiovascular phenotype

Benign:1

Nov 16, 2023

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

CardioboostCm

Benign

0.0055

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.51

CADD

Benign

0.0080

(source)

DANN

Benign

0.66

DEOGEN2

Uncertain

0.58

D;.

FATHMM_MKL

Benign

0.046

LIST_S2

Benign

0.33

T;T

M_CAP

Pathogenic

0.98

MetaRNN

Benign

0.034

T;T

MetaSVM

Pathogenic

1.9

MutationAssessor

Benign

-0.55

N;.

PhyloP100

-0.93

PrimateAI

Benign

0.25

PROVEAN

Benign

0.88

N;.

REVEL

Benign

0.17

Sift

Benign

1.0

T;.

Sift4G

Benign

0.90

T;.

Polyphen

0.0010

B;.

Vest4

0.058

MVP

0.40

MPC

0.68

ClinPred

0.014

GERP RS

-8.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.43

Mutation Taster

=91/9

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over