rs61752971
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP3BP6_Very_StrongBS1BS2
The NM_000276.4(OCRL):c.439+3A>G variant causes a splice donor 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. Variant has been reported in ClinVar as Likely benign (★★).
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_donor_region, intron
NM_000276.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.9996
2
Clinical Significance
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -15 ACMG points.
PP3
?
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
BP6
?
Variant X-129557953-A-G is Benign according to our data. Variant chrX-129557953-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 92725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. 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. This position pass quality control queck.
BS2
?
High Hemizygotes in GnomAd at 60 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
OCRL | NM_000276.4 | c.439+3A>G | splice_donor_region_variant, intron_variant | ENST00000371113.9 | |||
OCRL | NM_001318784.2 | c.442+3A>G | splice_donor_region_variant, intron_variant | ||||
OCRL | NM_001587.4 | c.439+3A>G | splice_donor_region_variant, intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
OCRL | ENST00000371113.9 | c.439+3A>G | splice_donor_region_variant, intron_variant | 1 | NM_000276.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00245 AC: 275AN: 112177Hom.: 0 Cov.: 23 AF XY: 0.00175 AC XY: 60AN XY: 34337
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GnomAD3 exomes AF: 0.00240 AC: 440AN: 183361Hom.: 0 AF XY: 0.00265 AC XY: 180AN XY: 67853
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GnomAD4 exome AF: 0.00344 AC: 3518AN: 1023809Hom.: 2 Cov.: 23 AF XY: 0.00337 AC XY: 1015AN XY: 301535
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GnomAD4 genome ? AF: 0.00245 AC: 275AN: 112228Hom.: 0 Cov.: 23 AF XY: 0.00174 AC XY: 60AN XY: 34398
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Uncertain:1Benign:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:4
Likely benign, no assertion criteria provided | clinical testing | Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | - | - - |
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 | CeGaT Center for Human Genetics Tuebingen | Nov 01, 2023 | OCRL: PP3, BS2 - |
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
not specified Benign:3
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 | - - |
Benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Lowe syndrome Benign:2
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Benign, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
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:
Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
Cadd
Benign
Dann
Benign
Splicing
Name
Calibrated prediction
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dbscSNV1_ADA
Pathogenic
dbscSNV1_RF
Pathogenic
SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: -3
Find out detailed SpliceAI scores and Pangolin per-transcript scores at