rs138260625

Positions:

chrX-129561251-G-A

Variant summary

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

The NM_000276.4(OCRL):c.897G>A(p.Met299Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00163 in 1,205,463 control chromosomes in the GnomAD database, including 34 homozygotes. There are 571 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 5 hom., 128 hem., cov: 23)

Exomes 𝑓: 0.0015 ( 29 hom. 443 hem. )

Consequence

OCRL
NM_000276.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.00900

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=0.0028491616).

BP6

Variant X-129561251-G-A is Benign according to our data. Variant chrX-129561251-G-A is described in ClinVar as [Benign]. Clinvar id is 129851.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00297 (333/111997) while in subpopulation AMR AF= 0.0298 (315/10567). AF 95% confidence interval is 0.0271. There are 5 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCRL	NM_000276.4 linkuse as main transcript	c.897G>A	p.Met299Ile	missense_variant	10/24	ENST00000371113.9	NP_000267.2	Q01968-1
OCRL	NM_001318784.2 linkuse as main transcript	c.900G>A	p.Met300Ile	missense_variant	10/24		NP_001305713.1	Q504W7
OCRL	NM_001587.4 linkuse as main transcript	c.897G>A	p.Met299Ile	missense_variant	10/23		NP_001578.2	Q01968-2A0A2X0TVZ9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9 linkuse as main transcript	c.897G>A	p.Met299Ile	missense_variant	10/24	1	NM_000276.4	ENSP00000360154.4		Q01968-1
OCRL	ENST00000357121.5 linkuse as main transcript	c.897G>A	p.Met299Ile	missense_variant	10/23	1		ENSP00000349635.5		Q01968-2

Frequencies

GnomAD3 genomes

AF:

0.00297

AC:

333

AN:

111942

Hom.:

Cov.:

AF XY:

0.00375

AC XY:

128

AN XY:

34148

show subpopulations

Gnomad AFR

AF:

0.000519

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0298

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:

0.0000188

Gnomad OTH

AF:

0.000663

GnomAD3 exomes

AF:

0.00770

AC:

1413

AN:

183404

Hom.:

AF XY:

0.00538

AC XY:

365

AN XY:

67878

show subpopulations

Gnomad AFR exome

AF:

0.000152

Gnomad AMR exome

AF:

0.0505

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000244

Gnomad OTH exome

AF:

0.00574

GnomAD4 exome

AF:

0.00149

AC:

1630

AN:

1093466

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

443

AN XY:

359116

show subpopulations

Gnomad4 AFR exome

AF:

0.000190

Gnomad4 AMR exome

AF:

0.0445

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000143

Gnomad4 OTH exome

AF:

0.00100

GnomAD4 genome

AF:

0.00297

AC:

333

AN:

111997

Hom.:

Cov.:

AF XY:

0.00374

AC XY:

128

AN XY:

34213

show subpopulations

Gnomad4 AFR

AF:

0.000518

Gnomad4 AMR

AF:

0.0298

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000188

Gnomad4 OTH

AF:

0.000655

Alfa

AF:

0.000411

Hom.:

Bravo

AF:

0.00548

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00544

AC:

660

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Apr 18, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 08, 2015	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Lowe syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Nephrolithiasis/nephrocalcinosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 24, 2016

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. -

OCRL-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 29, 2019

This variant is classified as 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

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Uncertain

0.57

D;.

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.84

T;D

MetaRNN

Benign

0.0028

T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.73

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

-1.8

N;N

REVEL

Benign

0.12

Sift

Benign

0.057

T;T

Sift4G

Uncertain

0.047

D;D

Polyphen

0.0

B;B

Vest4

0.15

MutPred

0.41

Loss of disorder (P = 0.0745);Loss of disorder (P = 0.0745);

MVP

0.67

MPC

1.3

ClinPred

0.017

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.20

gMVP

0.61

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