rs2071228

Positions:

Variant summary

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

The NM_000169.3(GLA):c.1000-22C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.202 in 1,194,299 control chromosomes in the GnomAD database, including 24,964 homozygotes. There are 78,455 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.33 ( 7174 hom., 10814 hem., cov: 24)

Exomes 𝑓: 0.19 ( 17790 hom. 67641 hem. )

Consequence

GLA
NM_000169.3 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.27

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:

GLA (HGNC:):

GLA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant X-101398121-G-A is Benign according to our data. Variant chrX-101398121-G-A is described in ClinVar as [Benign]. Clinvar id is 222112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101398121-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.74 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLA	NM_000169.3 linkuse as main transcript	c.1000-22C>T		intron_variant		ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.1000-22C>T		intron_variant		1	NM_000169.3	ENSP00000218516.4		P06280
RPL36A-HNRNPH2	ENST00000409170.3 linkuse as main transcript	c.300+2664G>A		intron_variant		4		ENSP00000386655.4		H7BZ11

Frequencies

GnomAD3 genomes

AF:

0.329

AC:

36769

AN:

111857

Hom.:

7167

Cov.:

AF XY:

0.316

AC XY:

10766

AN XY:

34037

show subpopulations

Gnomad AFR

AF:

0.748

Gnomad AMI

AF:

0.108

Gnomad AMR

AF:

0.244

Gnomad ASJ

AF:

0.140

Gnomad EAS

AF:

0.129

Gnomad SAS

AF:

0.431

Gnomad FIN

AF:

0.0976

Gnomad MID

AF:

0.198

Gnomad NFE

AF:

0.154

Gnomad OTH

AF:

0.275

GnomAD3 exomes

AF:

0.241

AC:

43681

AN:

181209

Hom.:

5568

AF XY:

0.231

AC XY:

15359

AN XY:

66537

show subpopulations

Gnomad AFR exome

AF:

0.759

Gnomad AMR exome

AF:

0.293

Gnomad ASJ exome

AF:

0.138

Gnomad EAS exome

AF:

0.128

Gnomad SAS exome

AF:

0.435

Gnomad FIN exome

AF:

0.102

Gnomad NFE exome

AF:

0.152

Gnomad OTH exome

AF:

0.203

GnomAD4 exome

AF:

0.188

AC:

203964

AN:

1082383

Hom.:

17790

Cov.:

AF XY:

0.194

AC XY:

67641

AN XY:

349521

show subpopulations

Gnomad4 AFR exome

AF:

0.763

Gnomad4 AMR exome

AF:

0.290

Gnomad4 ASJ exome

AF:

0.144

Gnomad4 EAS exome

AF:

0.130

Gnomad4 SAS exome

AF:

0.419

Gnomad4 FIN exome

AF:

0.103

Gnomad4 NFE exome

AF:

0.157

Gnomad4 OTH exome

AF:

0.219

GnomAD4 genome

AF:

0.329

AC:

36826

AN:

111916

Hom.:

7174

Cov.:

AF XY:

0.317

AC XY:

10814

AN XY:

34106

show subpopulations

Gnomad4 AFR

AF:

0.748

Gnomad4 AMR

AF:

0.244

Gnomad4 ASJ

AF:

0.140

Gnomad4 EAS

AF:

0.128

Gnomad4 SAS

AF:

0.429

Gnomad4 FIN

AF:

0.0976

Gnomad4 NFE

AF:

0.154

Gnomad4 OTH

AF:

0.279

Alfa

AF:

0.179

Hom.:

14507

Bravo

AF:

0.358

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 22, 2015	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 16, 2020	Variant summary: GLA c.1000-22C>T is located at a position not widely known to affect splicing. The variant allele was found at a frequency of 0.24 in 181209 control chromosomes in the gnomAD database, including 5568 homozygotes. The observed variant frequency is approximately 48.21 fold of the estimated maximal expected allele frequency for a pathogenic variant in GLA causing Fabry Disease phenotype (0.005), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.1000-22C>T in individuals affected with Fabry Disease and no experimental evidence demonstrating its impact on protein function have been reported. 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/likely benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Fabry disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

DANN

Benign

0.61

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