rs2071225

chrX-101407913-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000169.3(GLA):c.-10C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0733 in 1,201,243 control chromosomes in the GnomAD database, including 2,804 homozygotes. There are 31,097 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 0.070 (208 hom., 2527 hem., cov: 23)
  • Exomes 𝑓: 0.074 (2596 hom. 28570 hem.)
• Consequence: GLA NM_000169.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:18
• Conservation: PhyloP100: -0.554

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]

RPL36A-HNRNPH2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant X-101407913-G-A is Benign according to our data. Variant chrX-101407913-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 36280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407913-G-A is described in Lovd as [Benign]. Variant chrX-101407913-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.261 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.-10C>T		5_prime_UTR_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4023G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.-10C>T		5_prime_UTR_variant	1/7	1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.0700 AC: 7839 AN: 111984 Hom.: 209 Cov.: 23 AF XY: 0.0739 AC XY: 2524 AN XY: 34166

Gnomad AFR AF: 0.0671

Gnomad AMI AF: 0.0968

Gnomad AMR AF: 0.0730

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0793

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.0641

Gnomad MID AF: 0.0462

Gnomad NFE AF: 0.0611

Gnomad OTH AF: 0.0677

GnomAD3 exomes AF: 0.0932 AC: 17056 AN: 182908 Hom.: 754 AF XY: 0.0995 AC XY: 6711 AN XY: 67418

Gnomad AFR exome AF: 0.0670

Gnomad AMR exome AF: 0.116

Gnomad ASJ exome AF: 0.0510

Gnomad EAS exome AF: 0.0768

Gnomad SAS exome AF: 0.282

Gnomad FIN exome AF: 0.0633

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0816

GnomAD4 exome AF: 0.0736 AC: 80193 AN: 1089205 Hom.: 2596 Cov.: 31 AF XY: 0.0804 AC XY: 28570 AN XY: 355297

Gnomad4 AFR exome AF: 0.0712

Gnomad4 AMR exome AF: 0.111

Gnomad4 ASJ exome AF: 0.0516

Gnomad4 EAS exome AF: 0.0781

Gnomad4 SAS exome AF: 0.266

Gnomad4 FIN exome AF: 0.0645

Gnomad4 NFE exome AF: 0.0603

Gnomad4 OTH exome AF: 0.0785

GnomAD4 genome AF: 0.0699 AC: 7833 AN: 112038 Hom.: 208 Cov.: 23 AF XY: 0.0738 AC XY: 2527 AN XY: 34230

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.0731

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.0792

Gnomad4 SAS AF: 0.278

Gnomad4 FIN AF: 0.0641

Gnomad4 NFE AF: 0.0611

Gnomad4 OTH AF: 0.0682

Alfa AF: 0.0632 Hom.: 646

Bravo AF: 0.0696

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:18

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 12, 2013	-10C>T in 5'UTR of GLA: This variant is not expected to have clinical significan ce because it has been identified in 6.7% (256/3835) of African American chromos omes from a broad population by the NHLBI Exome Sequencing Project (http://evs.g s.washington.edu/EVS/; dbSNP rs2071225). -10C>T in 5'UTR of GLA (rs2071225; all ele frequency = 6.7%, 256/3835) ** -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 06, 2018	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided Benign:5

Likely 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	Mayo Clinic Laboratories, Mayo Clinic	Dec 15, 2015	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 19, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 14, 2020	This variant is associated with the following publications: (PMID: 21092187, 21896204, 18979223, 26981927, 25281798, 26334996, 25772321, 23677059, 22682330, 21683120, 8411052, 26070511, 29794742, 31996269) -

Fabry disease Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	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 was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 19, 2018	- -

Cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Aug 18, 2011

- -

Hypertrophic cardiomyopathy Benign:1

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	-0.60
Cadd	Benign	4.3
Dann	Benign	0.79

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

Other links and lift over

dbSNP: rs2071225; hg19: chrX-100662901; COSMIC: COSV54509325; COSMIC: COSV54509325;