rs61752970

chrX-129540745-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14A) has been classified as Uncertain significance.

• 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 2.14

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	2/24	ENST00000371113.9
OCRL	NM_001318784.2	c.44C>T	p.Thr15Ile	missense_variant	2/24
OCRL	NM_001587.4	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	2/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.41C>T	p.Thr14Ile	missense_variant, splice_region_variant	2/24	1	NM_000276.4	P1

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 534 AN: 110771 Hom.: 2 Cov.: 22 AF XY: 0.00449 AC XY: 148 AN XY: 32975

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.: 3 AF XY: 0.00612 AC XY: 415 AN XY: 67778

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.: 21 Cov.: 30 AF XY: 0.00685 AC XY: 2468 AN XY: 360456

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.: 2 Cov.: 22 AF XY: 0.00448 AC XY: 148 AN XY: 33034

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: 28

ALSPAC AF: 0.00900 AC: 26

ESP6500AA AF: 0.000782 AC: 3

ESP6500EA AF: 0.00535 AC: 36

ExAC AF: 0.00562 AC: 682

EpiCase AF: 0.00654

EpiControl AF: 0.00865

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:5

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 19, 2020	- -

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 11, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2016	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Lowe syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Nephrolithiasis/nephrocalcinosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 16, 2017

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	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	22
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;.
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.41	T;T
MetaRNN	Benign	0.0048	T;T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.55	D;D
PrimateAI	Uncertain	0.76	T
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	T
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

Other links and lift over

dbSNP: rs61752970; hg19: chrX-128674722; COSMIC: COSV105254410; COSMIC: COSV105254410;