rs2071226

chrX-101407693-T-C

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.194+17A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00479 in 1,188,364 control chromosomes in the GnomAD database, including 231 homozygotes. There are 1,864 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (28 hom., 190 hem., cov: 24)
  • Exomes 𝑓: 0.0048 (203 hom. 1674 hem.)
• Consequence: GLA NM_000169.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0110

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=-0.73).
• BP6: Variant X-101407693-T-C is Benign according to our data. Variant chrX-101407693-T-C is described in ClinVar as [Benign]. Clinvar id is 193058.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407693-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.115 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLA	NM_000169.3	c.194+17A>G		intron_variant		ENST00000218516.4
RPL36A-HNRNPH2	NM_001199973.2	c.301-4243T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4	c.194+17A>G		intron_variant		1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.00511 AC: 566 AN: 110784 Hom.: 28 Cov.: 24 AF XY: 0.00573 AC XY: 190 AN XY: 33150

Gnomad AFR AF: 0.000132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00391

Gnomad ASJ AF: 0.000380

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.00531

Gnomad FIN AF: 0.00645

Gnomad MID AF: 0.00424

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00470

GnomAD3 exomes AF: 0.0109 AC: 1992 AN: 182637 Hom.: 74 AF XY: 0.0100 AC XY: 678 AN XY: 67501

Gnomad AFR exome AF: 0.000152

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.125

Gnomad SAS exome AF: 0.00419

Gnomad FIN exome AF: 0.00581

Gnomad NFE exome AF: 0.000678

Gnomad OTH exome AF: 0.00331

GnomAD4 exome AF: 0.00475 AC: 5121 AN: 1077524 Hom.: 203 Cov.: 29 AF XY: 0.00485 AC XY: 1674 AN XY: 345174

Gnomad4 AFR exome AF: 0.000192

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.000260

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.00464

Gnomad4 FIN exome AF: 0.00641

Gnomad4 NFE exome AF: 0.000267

Gnomad4 OTH exome AF: 0.00903

GnomAD4 genome AF: 0.00512 AC: 567 AN: 110840 Hom.: 28 Cov.: 24 AF XY: 0.00572 AC XY: 190 AN XY: 33216

Gnomad4 AFR AF: 0.000131

Gnomad4 AMR AF: 0.00391

Gnomad4 ASJ AF: 0.000380

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.00571

Gnomad4 FIN AF: 0.00645

Gnomad4 NFE AF: 0.000398

Gnomad4 OTH AF: 0.00531

Alfa AF: 0.00154 Hom.: 47

Bravo AF: 0.00619

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

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	Eurofins Ntd Llc (ga)	Feb 07, 2017	- -
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	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 03, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	12
Dann	Benign	0.71

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: rs2071226; hg19: chrX-100662681; COSMIC: COSV54509725; COSMIC: COSV54509725;