chrX-101407915-C-T

Position:

chrX-101407915-C-T

Variant summary

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

The NM_000169.3(GLA):c.-12G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0423 in 1,200,657 control chromosomes in the GnomAD database, including 1,251 homozygotes. There are 16,901 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.066 ( 281 hom., 2123 hem., cov: 23)

Exomes 𝑓: 0.040 ( 970 hom. 14778 hem. )

Consequence

GLA
NM_000169.3 5_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: -0.576

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

Computational evidence support a benign effect (BayesDel_noAF=-0.61).

BP6

Variant X-101407915-C-T is Benign according to our data. Variant chrX-101407915-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 42449.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407915-C-T is described in Lovd as [Benign]. Variant chrX-101407915-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.138 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.-12G>A		5_prime_UTR_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.301-4021C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript	c.-12G>A		5_prime_UTR_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0658

AC:

7361

AN:

111875

Hom.:

280

Cov.:

AF XY:

0.0619

AC XY:

2110

AN XY:

34069

show subpopulations

Gnomad AFR

AF:

0.142

Gnomad AMI

AF:

0.0116

Gnomad AMR

AF:

0.0895

Gnomad ASJ

AF:

0.00869

Gnomad EAS

AF:

0.0377

Gnomad SAS

AF:

0.117

Gnomad FIN

AF:

0.00717

Gnomad MID

AF:

0.0335

Gnomad NFE

AF:

0.0271

Gnomad OTH

AF:

0.0693

GnomAD3 exomes

AF:

0.0607

AC:

11095

AN:

182916

Hom.:

411

AF XY:

0.0577

AC XY:

3895

AN XY:

67450

show subpopulations

Gnomad AFR exome

AF:

0.140

Gnomad AMR exome

AF:

0.134

Gnomad ASJ exome

AF:

0.0131

Gnomad EAS exome

AF:

0.0398

Gnomad SAS exome

AF:

0.114

Gnomad FIN exome

AF:

0.0101

Gnomad NFE exome

AF:

0.0288

Gnomad OTH exome

AF:

0.0531

GnomAD4 exome

AF:

0.0398

AC:

43354

AN:

1088727

Hom.:

970

Cov.:

AF XY:

0.0417

AC XY:

14778

AN XY:

354697

show subpopulations

Gnomad4 AFR exome

AF:

0.147

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.0138

Gnomad4 EAS exome

AF:

0.0461

Gnomad4 SAS exome

AF:

0.115

Gnomad4 FIN exome

AF:

0.00948

Gnomad4 NFE exome

AF:

0.0293

Gnomad4 OTH exome

AF:

0.0453

GnomAD4 genome

AF:

0.0659

AC:

7374

AN:

111930

Hom.:

281

Cov.:

AF XY:

0.0622

AC XY:

2123

AN XY:

34134

show subpopulations

Gnomad4 AFR

AF:

0.142

Gnomad4 AMR

AF:

0.0892

Gnomad4 ASJ

AF:

0.00869

Gnomad4 EAS

AF:

0.0378

Gnomad4 SAS

AF:

0.117

Gnomad4 FIN

AF:

0.00717

Gnomad4 NFE

AF:

0.0271

Gnomad4 OTH

AF:

0.0678

Alfa

AF:

0.0487

Hom.:

465

Bravo

AF:

0.0764

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 17, 2012	-12G>A in the 5' UTR of GLA: This variant is not expected to have clinical signi ficance because it has been identified in 14.5% (467/3216) of African American c hromosomes from a broad population by the NHLBI Exome Sequencing Project (http:/ /evs.gs.washington.edu/EVS/; dbSNP rs3027585) -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 11, 2018	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Fabry disease

Benign:4

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 15, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 19, 2018	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not provided

Benign:3

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 30, 2016	- -
Likely 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	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 25772321) -

Hypertrophic cardiomyopathy

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.81

DANN

Benign

0.75

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