rs397515872

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_000169.3(GLA):c.714T>C(p.Ser238Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,206,302 control chromosomes in the GnomAD database, including 1 homozygotes. There are 4 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).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000013 ( 1 hom. 4 hem. )

Consequence

GLA
NM_000169.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.544

Publications

0 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.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant X-101398872-A-G is Benign according to our data. Variant chrX-101398872-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 42460.We mark this variant Benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

BP7

Synonymous conserved (PhyloP=0.544 with no splicing effect.

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.714T>C	p.Ser238Ser	synonymous_variant	Exon 5 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.714T>C	p.Ser238Ser	synonymous_variant	Exon 5 of 7	1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 link	c.300+3415A>G		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.0000356

AC:

AN:

112330

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000324

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000189

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000164

AC:

AN:

183483

AF XY:

0.0000294

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 FIN exome

AF:

0.0000625

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000128

AC:

AN:

1093972

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

359450

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26322

American (AMR)

AF:

0.0000284

AC:

AN:

35202

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19365

East Asian (EAS)

AF:

0.00

AC:

AN:

30194

South Asian (SAS)

AF:

0.00

AC:

AN:

54058

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40531

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4095

European-Non Finnish (NFE)

AF:

0.00000954

AC:

AN:

838258

Other (OTH)

AF:

0.000109

AC:

AN:

45947

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.438

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000356

AC:

AN:

112330

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34480

show subpopulations

African (AFR)

AF:

0.0000324

AC:

AN:

30880

American (AMR)

AF:

0.000189

AC:

AN:

10587

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3590

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6155

Middle Eastern (MID)

AF:

0.00

AC:

AN:

238

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53300

Other (OTH)

AF:

0.00

AC:

AN:

1517

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.538

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000227

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Fabry disease

Benign:3

Jul 15, 2021

Genome-Nilou Lab

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 22, 2019

Color Diagnostics, LLC DBA Color Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Uncertain:1Benign:1

Sep 18, 2018

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Feb 12, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

p.Ser238Ser in exon 5 of GLA: This variant is not expected to have clinical sign ificance because it does not alter an amino acid residue and is not located with in the splice consensus sequence. It has been identified in 1/87762 of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP87762). -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Cardiomyopathy

Benign:1

Mar 15, 2023

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GLA-related disorder

Benign:1

Sep 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype

Benign:1

Mar 04, 2020

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

BayesDel_noAF

Benign

-0.71

CADD

Benign

9.2

(source)

DANN

Benign

0.69

PhyloP100

0.54

Mutation Taster

=100/0

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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rs397515872

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