rs3027585

Positions:

• chrX-101407915-C-T

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.-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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -0.576

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=-0.61).
• 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	c.-12G>A		5_prime_UTR_variant	1/7	ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4021C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	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.: 23 AF XY: 0.0619 AC XY: 2110 AN XY: 34069

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

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.: 30 AF XY: 0.0417 AC XY: 14778 AN XY: 354697

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.: 23 AF XY: 0.0622 AC XY: 2123 AN XY: 34134

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

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

Other links and lift over

dbSNP: rs3027585; hg19: chrX-100662903; COSMIC: COSV54509333; COSMIC: COSV54509333;