chrX-101407933-C-T

Position:

chrX-101407933-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001199973.2(RPL36A-HNRNPH2):c.301-4003C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,149,952 control chromosomes in the GnomAD database, including 77 homozygotes. There are 4,453 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 0.0084 ( 2 hom., 236 hem., cov: 23)

Exomes 𝑓: 0.013 ( 75 hom. 4217 hem. )

Consequence

RPL36A-HNRNPH2
NM_001199973.2 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.648

Variant links:

Genes affected

RPL36A-HNRNPH2 (HGNC:):

RPL36A-HNRNPH2 links:

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:

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=-0.56).

BP6

Variant X-101407933-C-T is Benign according to our data. Variant chrX-101407933-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 218430.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-101407933-C-T is described in Lovd as [Pathogenic]. Variant chrX-101407933-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome allele frequency = 0.0132 (13732/1037831) while in subpopulation NFE AF= 0.0154 (12142/788041). AF 95% confidence interval is 0.0152. There are 75 homozygotes in gnomad4_exome. There are 4217 alleles in male gnomad4_exome subpopulation. Median coverage is 27. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPL36A-HNRNPH2	NM_001199973.2 linkuse as main transcript	c.301-4003C>T		intron_variant
GLA	NM_000169.3 linkuse as main transcript			upstream_gene_variant		ENST00000218516.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLA	ENST00000218516.4 linkuse as main transcript			upstream_gene_variant		1	NM_000169.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00843

AC:

945

AN:

112067

Hom.:

Cov.:

AF XY:

0.00689

AC XY:

236

AN XY:

34241

show subpopulations

Gnomad AFR

AF:

0.00152

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00470

Gnomad ASJ

AF:

0.0102

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00185

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00840

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.00930

GnomAD3 exomes

AF:

0.00863

AC:

1570

AN:

181938

Hom.:

AF XY:

0.00875

AC XY:

584

AN XY:

66726

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00190

Gnomad ASJ exome

AF:

0.00994

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00437

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0104

GnomAD4 exome

AF:

0.0132

AC:

13732

AN:

1037831

Hom.:

Cov.:

AF XY:

0.0136

AC XY:

4217

AN XY:

310627

show subpopulations

Gnomad4 AFR exome

AF:

0.00171

Gnomad4 AMR exome

AF:

0.00230

Gnomad4 ASJ exome

AF:

0.00935

Gnomad4 EAS exome

AF:

0.0000668

Gnomad4 SAS exome

AF:

0.00454

Gnomad4 FIN exome

AF:

0.0135

Gnomad4 NFE exome

AF:

0.0154

Gnomad4 OTH exome

AF:

0.0111

GnomAD4 genome

AF:

0.00842

AC:

944

AN:

112121

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

236

AN XY:

34305

show subpopulations

Gnomad4 AFR

AF:

0.00152

Gnomad4 AMR

AF:

0.00470

Gnomad4 ASJ

AF:

0.0102

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00185

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0138

Gnomad4 OTH

AF:

0.00918

Alfa

AF:

0.0109

Hom.:

Bravo

AF:

0.00775

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Fabry disease

Benign:5

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Mar 06, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 11, 2015	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 23, 2022	- -

not specified

Benign:2

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:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 18979223, 9323559, 7672123, 25772321) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.2

DANN

Benign

0.86

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