X-101398962-T-C

Position:

chrX-101398962-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000169.3(GLA):c.640-16A>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 1,180,033 control chromosomes in the GnomAD database, including 7,341 homozygotes. There are 50,881 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.13 ( 682 hom., 4319 hem., cov: 23)

Exomes 𝑓: 0.13 ( 6659 hom. 46562 hem. )

Consequence

GLA
NM_000169.3 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.649

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 Benign. Variant got -20 ACMG points.

BP4

This place is a probable branch point but likely benign (scored 1 / 10). Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BP6

Variant X-101398962-T-C is Benign according to our data. Variant chrX-101398962-T-C is described in ClinVar as [Benign]. Clinvar id is 92559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398962-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.640-16A>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.300+3505T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.640-16A>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

AF:

0.128

AC:

14288

AN:

111891

Hom.:

682

Cov.:

AF XY:

0.126

AC XY:

4308

AN XY:

34081

show subpopulations

Gnomad AFR

AF:

0.147

Gnomad AMI

AF:

0.0768

Gnomad AMR

AF:

0.0998

Gnomad ASJ

AF:

0.133

Gnomad EAS

AF:

0.0871

Gnomad SAS

AF:

0.310

Gnomad FIN

AF:

0.0901

Gnomad MID

AF:

0.139

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.103

GnomAD3 exomes

AF:

0.141

AC:

25883

AN:

183214

Hom.:

1381

AF XY:

0.148

AC XY:

10022

AN XY:

67718

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.136

Gnomad ASJ exome

AF:

0.125

Gnomad EAS exome

AF:

0.0849

Gnomad SAS exome

AF:

0.324

Gnomad FIN exome

AF:

0.0923

Gnomad NFE exome

AF:

0.120

Gnomad OTH exome

AF:

0.130

GnomAD4 exome

AF:

0.131

AC:

139866

AN:

1068089

Hom.:

6659

Cov.:

AF XY:

0.138

AC XY:

46562

AN XY:

338483

show subpopulations

Gnomad4 AFR exome

AF:

0.152

Gnomad4 AMR exome

AF:

0.131

Gnomad4 ASJ exome

AF:

0.129

Gnomad4 EAS exome

AF:

0.0815

Gnomad4 SAS exome

AF:

0.307

Gnomad4 FIN exome

AF:

0.0933

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.136

GnomAD4 genome

AF:

0.128

AC:

14297

AN:

111944

Hom.:

682

Cov.:

AF XY:

0.126

AC XY:

4319

AN XY:

34144

show subpopulations

Gnomad4 AFR

AF:

0.148

Gnomad4 AMR

AF:

0.0998

Gnomad4 ASJ

AF:

0.133

Gnomad4 EAS

AF:

0.0868

Gnomad4 SAS

AF:

0.309

Gnomad4 FIN

AF:

0.0901

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.103

Alfa

AF:

0.133

Hom.:

1132

Bravo

AF:

0.129

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:7

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 17, 2018	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2020	Variant summary: GLA c.640-16A>G alters a nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.14 in 183214 control chromosomes in the gnomAD database, including 1381 homozygotes. The observed variant frequency is approximately 19.98 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLA causing Cardiomyopathy phenotype (0.0071), strongly suggesting that the variant is benign. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Fabry disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -

Hypertrophic cardiomyopathy

Benign:1

Benign, no assertion criteria provided

clinical testing

Cohesion Phenomics

Sep 29, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

0.061

DANN

Benign

0.36

BranchPoint Hunter

1.0

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