X-129540450-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.11C>T(p.Pro4Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000209 in 1,150,269 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.000084 ( 0 hom., 3 hem., cov: 21)

Exomes 𝑓: 0.000014 ( 0 hom. 4 hem. )

Consequence

OCRL
NM_000276.4 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -1.39

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=0.0400469).

BP6

Variant X-129540450-C-T is Benign according to our data. Variant chrX-129540450-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 976515.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000835 (9/107742) while in subpopulation EAS AF= 0.00269 (9/3345). AF 95% confidence interval is 0.0014. There are 0 homozygotes in gnomad4. There are 3 alleles in male gnomad4 subpopulation. Median coverage is 21. This position pass quality control queck.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 24	ENST00000371113.9	NP_000267.2	Q01968-1
OCRL	NM_001318784.2 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 24		NP_001305713.1	Q504W7
OCRL	NM_001587.4 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 23		NP_001578.2	Q01968-2A0A2X0TVZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
OCRL	ENST00000371113.9 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 24	1	NM_000276.4	ENSP00000360154.4	Q01968-1
OCRL	ENST00000357121.5 link	c.11C>T	p.Pro4Leu	missense_variant	Exon 1 of 23	1		ENSP00000349635.5	Q01968-2
OCRL	ENST00000691455.1 link	n.11C>T		non_coding_transcript_exon_variant	Exon 1 of 18			ENSP00000510265.1	A0A8I5KYX7
OCRL	ENST00000486673.1 link	n.91+511C>T		intron_variant	Intron 1 of 7	5

Frequencies

GnomAD3 genomes

AF:

0.0000835

AC:

AN:

107742

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

30294

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000188

AC:

AN:

95695

Hom.:

AF XY:

0.000199

AC XY:

AN XY:

35109

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00233

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1042527

Hom.:

Cov.:

AF XY:

0.0000118

AC XY:

AN XY:

340131

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000371

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000245

Gnomad4 OTH exome

AF:

0.0000681

GnomAD4 genome

AF:

0.0000835

AC:

AN:

107742

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

30294

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00269

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000604

ExAC

AF:

0.000126

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Lowe syndrome

Benign:1

Nov 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nephrolithiasis/nephrocalcinosis

Benign:1

Dec 27, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely 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. -

Lowe syndrome;C1845167:Dent disease type 2

Benign:1

Nov 04, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

T;.

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.72

T;T

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.040

T;T

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.69

N;N

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.30

N;N

REVEL

Benign

0.24

Sift

Benign

0.082

T;T

Sift4G

Benign

0.33

T;T

Polyphen

0.025

B;B

Vest4

0.11

MutPred

0.18

Loss of glycosylation at P4 (P = 0.0265);Loss of glycosylation at P4 (P = 0.0265);

MVP

0.60

MPC

0.27

ClinPred

0.041

GERP RS

0.25

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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