chrX-129540745-C-T

Variant names:

Variant summary

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

The NM_000276.4(OCRL):c.41C>T(p.Thr14Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,205,712 control chromosomes in the GnomAD database, including 23 homozygotes. There are 2,616 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0048 ( 2 hom., 148 hem., cov: 22)

Exomes 𝑓: 0.0071 ( 21 hom. 2468 hem. )

Consequence

OCRL
NM_000276.4 missense, splice_region

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

OCRL (HGNC:8108): (OCRL inositol polyphosphate-5-phosphatase) This gene encodes an inositol polyphosphate 5-phosphatase. This protein is involved in regulating membrane trafficking and is located in numerous subcellular locations including the trans-Golgi network, clathrin-coated vesicles and, endosomes and the plasma membrane. This protein may also play a role in primary cilium formation. Mutations in this gene cause oculocerebrorenal syndrome of Lowe and also Dent disease. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

OCRL 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 (MetaRNN=0.0047611).

BP6

Variant X-129540745-C-T is Benign according to our data. Variant chrX-129540745-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-129540745-C-T is described in Lovd as [Likely_benign]. Variant chrX-129540745-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00482 (534/110820) while in subpopulation NFE AF= 0.00746 (393/52690). AF 95% confidence interval is 0.00685. There are 2 homozygotes in gnomad4. There are 148 alleles in male gnomad4 subpopulation. Median coverage is 22. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4 link	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	Exon 2 of 24	ENST00000371113.9	NP_000267.2	Q01968-1
OCRL	NM_001318784.2 link	c.44C>T	p.Thr15Ile	missense_variant	Exon 2 of 24		NP_001305713.1	Q504W7
OCRL	NM_001587.4 link	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	Exon 2 of 23		NP_001578.2	Q01968-2A0A2X0TVZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9 link	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	Exon 2 of 24	1	NM_000276.4	ENSP00000360154.4		Q01968-1
OCRL	ENST00000357121.5 link	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	Exon 2 of 23	1		ENSP00000349635.5		Q01968-2

Frequencies

GnomAD3 genomes

AF:

0.00482

AC:

534

AN:

110771

Hom.:

Cov.:

AF XY:

0.00449

AC XY:

148

AN XY:

32975

show subpopulations

Gnomad AFR

AF:

0.00121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00171

Gnomad ASJ

AF:

0.000760

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00116

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00746

Gnomad OTH

AF:

0.00201

GnomAD3 exomes

AF:

0.00565

AC:

1036

AN:

183264

Hom.:

AF XY:

0.00612

AC XY:

415

AN XY:

67778

show subpopulations

Gnomad AFR exome

AF:

0.000989

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00173

Gnomad FIN exome

AF:

0.0179

Gnomad NFE exome

AF:

0.00760

Gnomad OTH exome

AF:

0.00575

GnomAD4 exome

AF:

0.00710

AC:

7775

AN:

1094892

Hom.:

Cov.:

AF XY:

0.00685

AC XY:

2468

AN XY:

360456

show subpopulations

Gnomad4 AFR exome

AF:

0.000722

Gnomad4 AMR exome

AF:

0.00202

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00174

Gnomad4 FIN exome

AF:

0.0172

Gnomad4 NFE exome

AF:

0.00789

Gnomad4 OTH exome

AF:

0.00533

GnomAD4 genome

AF:

0.00482

AC:

534

AN:

110820

Hom.:

Cov.:

AF XY:

0.00448

AC XY:

148

AN XY:

33034

show subpopulations

Gnomad4 AFR

AF:

0.00121

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.000760

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00116

Gnomad4 FIN

AF:

0.0131

Gnomad4 NFE

AF:

0.00746

Gnomad4 OTH

AF:

0.00198

Alfa

AF:

0.00651

Hom.:

275

Bravo

AF:

0.00396

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00900

AC:

ESP6500AA

AF:

0.000782

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00562

AC:

682

EpiCase

AF:

0.00654

EpiControl

AF:

0.00865

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

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

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

May 15, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 19, 2020

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified

Benign:4

Aug 11, 2014

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 12, 2016

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Lowe syndrome

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrolithiasis/nephrocalcinosis

Benign:1

Jan 16, 2017

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.

FATHMM_MKL

Benign

0.37

LIST_S2

Benign

0.41

T;T

MetaRNN

Benign

0.0048

T;T

MetaSVM

Uncertain

-0.013

MutationAssessor

Benign

1.0

L;L

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-0.67

N;N

REVEL

Benign

0.23

Sift

Uncertain

0.018

D;D

Sift4G

Benign

0.34

T;T

Polyphen

0.0

B;B

Vest4

0.15

MVP

0.75

MPC

0.27

ClinPred

0.0052

GERP RS

3.7

Varity_R

0.061

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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