chrX-129557953-A-G

Position:

chrX-129557953-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

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:2B:12

Conservation

PhyloP100: 5.32

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:

OCRL (HGNC:):

OCRL links:

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ACMG classification

Classification made for transcript

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	Effect	MANE	Protein	UniProt
OCRL	NM_000276.4 linkuse as main transcript	c.439+3A>G	splice_region_variant, intron_variant	ENST00000371113.9	NP_000267.2	Q01968-1
OCRL	NM_001318784.2 linkuse as main transcript	c.442+3A>G	splice_region_variant, intron_variant		NP_001305713.1	Q504W7
OCRL	NM_001587.4 linkuse as main transcript	c.439+3A>G	splice_region_variant, intron_variant		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.439+3A>G		splice_region_variant, intron_variant		1	NM_000276.4	ENSP00000360154.4		Q01968-1
OCRL	ENST00000357121.5 linkuse as main transcript	c.439+3A>G		splice_region_variant, intron_variant		1		ENSP00000349635.5		Q01968-2

Frequencies

GnomAD3 genomes

AF:

0.00245

AC:

275

AN:

112177

Hom.:

Cov.:

AF XY:

0.00175

AC XY:

AN XY:

34337

show subpopulations

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.:

AF XY:

0.00265

AC XY:

180

AN XY:

67853

show subpopulations

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.:

Cov.:

AF XY:

0.00337

AC XY:

1015

AN XY:

301535

show subpopulations

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.:

Cov.:

AF XY:

0.00174

AC XY:

AN XY:

34398

show subpopulations

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.:

Bravo

AF:

0.00196

EpiCase

AF:

0.00360

EpiControl

AF:

0.00344

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:12

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign: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

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

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