Genetic Variant OCRL:p.Pro4Leu (chrX-129540450-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -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. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P4P) has been classified 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

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

Dent disease type 2
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
oculocerebrorenal syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet

OCRL 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 (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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 21. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000276.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OCRL	NM_000276.4	MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 24	NP_000267.2
OCRL	NM_001318784.2		c.11C>T	p.Pro4Leu	missense	Exon 1 of 24	NP_001305713.1
OCRL	NM_001587.4		c.11C>T	p.Pro4Leu	missense	Exon 1 of 23	NP_001578.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OCRL	ENST00000371113.9	TSL:1 MANE Select	c.11C>T	p.Pro4Leu	missense	Exon 1 of 24	ENSP00000360154.4	Q01968-1
OCRL	ENST00000357121.5	TSL:1	c.11C>T	p.Pro4Leu	missense	Exon 1 of 23	ENSP00000349635.5	Q01968-2
OCRL	ENST00000949289.1		c.11C>T	p.Pro4Leu	missense	Exon 1 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes

AF:

0.0000835

AC:

AN:

107742

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.000188

AC:

AN:

95695

AF XY:

0.000199

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 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

African (AFR)

AF:

0.00

AC:

AN:

24725

American (AMR)

AF:

0.00

AC:

AN:

27822

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18529

East Asian (EAS)

AF:

0.000371

AC:

AN:

26989

South Asian (SAS)

AF:

0.00

AC:

AN:

49750

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29769

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2930

European-Non Finnish (NFE)

AF:

0.00000245

AC:

AN:

817958

Other (OTH)

AF:

0.0000681

AC:

AN:

44055

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000835

AC:

AN:

107742

Hom.:

Cov.:

AF XY:

0.0000990

AC XY:

AN XY:

30294

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29592

American (AMR)

AF:

0.00

AC:

AN:

10336

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2594

East Asian (EAS)

AF:

0.00269

AC:

AN:

3345

South Asian (SAS)

AF:

0.00

AC:

AN:

2297

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5676

Middle Eastern (MID)

AF:

0.00

AC:

AN:

231

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

51589

Other (OTH)

AF:

0.00

AC:

AN:

1434

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000126

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Lowe syndrome (1)

Lowe syndrome;C1845167:Dent disease type 2 (1)

Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.48

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.25

FATHMM_MKL

Benign

0.017

LIST_S2

Benign

0.72

M_CAP

Pathogenic

0.96

MetaRNN

Benign

0.040

MetaSVM

Benign

-0.48

MutationAssessor

Benign

0.69

PhyloP100

-1.4

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-0.30

REVEL

Benign

0.24

Sift

Benign

0.082

Sift4G

Benign

0.33

Polyphen

0.025

Vest4

0.11

MutPred

0.18

Loss of glycosylation at P4 (P = 0.0265)

MVP

0.60

MPC

0.27

ClinPred

0.041

GERP RS

0.25

PromoterAI

-0.042

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.054

gMVP

0.38

Mutation Taster

=99/1

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over