X-101397753-A-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001199973.2(RPL36A-HNRNPH2):c.300+2296A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00056 in 1,051,302 control chromosomes in the GnomAD database, including 1 homozygotes. There are 158 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 0.00022 (0 hom., 5 hem., cov: 23)
  • Exomes 𝑓: 0.00060 (1 hom. 153 hem.)
• Consequence: RPL36A-HNRNPH2 NM_001199973.2 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.07

Genes affected

RPL36A-HNRNPH2 (HGNC:):

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]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant X-101397753-A-C is Benign according to our data. Variant chrX-101397753-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3048387.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAd at 5 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL36A-HNRNPH2	NM_001199973.2	c.300+2296A>C		intron_variant
GLA	NM_000169.3			downstream_gene_variant		ENST00000218516.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4			downstream_gene_variant		1	NM_000169.3	P1

Frequencies

GnomAD3 genomes AF: 0.000222 AC: 25 AN: 112752 Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5 AN XY: 34912

Gnomad AFR AF: 0.0000644

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000188

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000375

Gnomad OTH AF: 0.000659

GnomAD4 exome AF: 0.000601 AC: 564 AN: 938496 Hom.: 1 Cov.: 17 AF XY: 0.000569 AC XY: 153 AN XY: 268802

Gnomad4 AFR exome AF: 0.0000428

Gnomad4 AMR exome AF: 0.000372

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000248

Gnomad4 NFE exome AF: 0.000762

Gnomad4 OTH exome AF: 0.000417

GnomAD4 genome AF: 0.000222 AC: 25 AN: 112806 Hom.: 0 Cov.: 23 AF XY: 0.000143 AC XY: 5 AN XY: 34976

Gnomad4 AFR AF: 0.0000642

Gnomad4 AMR AF: 0.000188

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000375

Gnomad4 OTH AF: 0.000651

Alfa AF: 0.000216 Hom.: 1

Bravo AF: 0.000242

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

GLA-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 27, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
Cadd	Benign	4.6
Dann	Benign	0.80

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: rs186392986; hg19: chrX-100652741;