rs61752971

Positions:

• chrX-129557953-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000276.4(OCRL):​c.439+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00334 in 1,136,037 control chromosomes in the GnomAD database, including 2 homozygotes. There are 1,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., 60 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (2 hom. 1015 hem.)
• Consequence: OCRL NM_000276.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:12
• Conservation: PhyloP100: 5.32

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant X-129557953-A-G is Benign according to our data. Variant chrX-129557953-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 92725.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=3}. Variant chrX-129557953-A-G is described in Lovd as [Benign]. Variant chrX-129557953-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00245 (275/112228) while in subpopulation NFE AF= 0.00372 (198/53228). AF 95% confidence interval is 0.00329. There are 0 homozygotes in gnomad4. There are 60 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 60 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCRL	NM_000276.4	c.439+3A>G		splice_region_variant, intron_variant		ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.442+3A>G		splice_region_variant, intron_variant			NP_001305713.1
OCRL	NM_001587.4	c.439+3A>G		splice_region_variant, intron_variant			NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.439+3A>G		splice_region_variant, intron_variant		1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.439+3A>G		splice_region_variant, intron_variant		1		ENSP00000349635.5

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 275 AN: 112177 Hom.: 0 Cov.: 23 AF XY: 0.00175 AC XY: 60 AN XY: 34337

Gnomad AFR AF: 0.000583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00188

Gnomad ASJ AF: 0.00341

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00396

GnomAD3 exomes AF: 0.00240 AC: 440 AN: 183361 Hom.: 0 AF XY: 0.00265 AC XY: 180 AN XY: 67853

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000943

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00344 AC: 3518 AN: 1023809 Hom.: 2 Cov.: 23 AF XY: 0.00337 AC XY: 1015 AN XY: 301535

Gnomad4 AFR exome AF: 0.000440

Gnomad4 AMR exome AF: 0.00102

Gnomad4 ASJ exome AF: 0.00201

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.00444

Gnomad4 NFE exome AF: 0.00397

Gnomad4 OTH exome AF: 0.00240

GnomAD4 genome AF: 0.00245 AC: 275 AN: 112228 Hom.: 0 Cov.: 23 AF XY: 0.00174 AC XY: 60 AN XY: 34398

Gnomad4 AFR AF: 0.000582

Gnomad4 AMR AF: 0.00188

Gnomad4 ASJ AF: 0.00341

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000370

Gnomad4 FIN AF: 0.00378

Gnomad4 NFE AF: 0.00372

Gnomad4 OTH AF: 0.00391

Alfa AF: 0.00204 Hom.: 15

Bravo AF: 0.00196

EpiCase AF: 0.00360

EpiControl AF: 0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:12

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	OCRL: PP3, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 16, 2024	Identified in a patient with atypical Dent disease who also harbored a frameshift variant in the CLCN5 gene in published literature (PMID: 23047739); Observed in hemizygous state in a patient with epilepsy in the literature and not observed in hemizygous state in controls (PMID: 31069529); RNA studies demonstrate a damaging effect: producing a fragment 90 bp shorter than expected with sequencing analysis being consistent with skipping of in-frame exon 6 (PMID: 23047739); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 34426522, 34680992, 31069529, 23047739) -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Nov 22, 2016	- -

Lowe syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Developmental cataract Uncertain:1

Uncertain significance, no assertion criteria provided

research

Eye Genetics Research Group, Children's Medical Research Institute

Jan 09, 2015

- -

Nephrolithiasis/nephrocalcinosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 29, 2017

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

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61752971; hg19: chrX-128691930;