X-101407933-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000409170.3(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
ENST00000409170.3 intron

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.648

Publications

16 publications found

Variant links:

Genes affected

RPL36A-HNRNPH2 (HGNC:48349): (RPL36A-HNRNPH2 readthrough) This locus represents naturally occurring read-through transcription between the neighboring ribosomal protein L36a and heterogeneous nuclear ribonucleoprotein H2 (H') genes on chromosome X. The read-through transcript produces a protein with similarity to the protein encoded by the upstream locus, ribosomal protein L36a. Alternatively spliced transcript variants have been identified. [provided by RefSeq, Jan 2011]

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 Gene-Disease associations (from GenCC):

Fabry disease
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, ClinGen, Orphanet, G2P, Labcorp Genetics (formerly Invitae)

GLA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 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 GnomAdExome4. There are 4217 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLA	NM_000169.3 link	c.-30G>A		upstream_gene_variant		ENST00000218516.4	NP_000160.1	P06280Q53Y83

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RPL36A-HNRNPH2	ENST00000409170.3 link	c.301-4003C>T		intron_variant	Intron 4 of 4	4		ENSP00000386655.4		H7BZ11
GLA	ENST00000218516.4 link	c.-30G>A		upstream_gene_variant		1	NM_000169.3	ENSP00000218516.4		P06280

Frequencies

GnomAD3 genomes

AF:

0.00843

AC:

945

AN:

112067

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.00863

AC:

1570

AN:

181938

AF XY:

0.00875

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 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

African (AFR)

AF:

0.00171

AC:

AN:

25210

American (AMR)

AF:

0.00230

AC:

AN:

35150

Ashkenazi Jewish (ASJ)

AF:

0.00935

AC:

178

AN:

19028

East Asian (EAS)

AF:

0.0000668

AC:

AN:

29942

South Asian (SAS)

AF:

0.00454

AC:

238

AN:

52392

European-Finnish (FIN)

AF:

0.0135

AC:

548

AN:

40494

Middle Eastern (MID)

AF:

0.00259

AC:

AN:

3470

European-Non Finnish (NFE)

AF:

0.0154

AC:

12142

AN:

788041

Other (OTH)

AF:

0.0111

AC:

491

AN:

44104

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

485

970

1455

1940

2425

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

458

916

1374

1832

2290

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00842

AC:

944

AN:

112121

Hom.:

Cov.:

AF XY:

0.00688

AC XY:

236

AN XY:

34305

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

30892

American (AMR)

AF:

0.00470

AC:

AN:

10646

Ashkenazi Jewish (ASJ)

AF:

0.0102

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3551

South Asian (SAS)

AF:

0.00185

AC:

AN:

2702

European-Finnish (FIN)

AF:

0.0105

AC:

AN:

6089

Middle Eastern (MID)

AF:

0.00922

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.0138

AC:

735

AN:

53161

Other (OTH)

AF:

0.00918

AC:

AN:

1525

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

121

161

201

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0101

Hom.:

149

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

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 23, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 11, 2015

Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Nov 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:2

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 18979223, 9323559, 7672123, 25772321) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

8.2

(source)

DANN

Benign

0.86

PhyloP100

-0.65

PromoterAI

0.054

Neutral

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over