rs935956958

Variant names:

• chrX-129588933-G-C
• rs935956958
• NM_000276.4:c.2389G>C

Your query was ambiguous. Multiple possible variants found:

• chrX-129588933-G-C
• chrX-129588933-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_000276.4(OCRL):​c.2389G>C​(p.Ala797Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.76
• Publications: 6 publications found

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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.942
• PP5: Variant X-129588933-G-C is Pathogenic according to our data. Variant chrX-129588933-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 567454.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.2389G>C	p.Ala797Pro	missense_variant	Exon 22 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.2392G>C	p.Ala798Pro	missense_variant	Exon 22 of 24		NP_001305713.1
OCRL	NM_001587.4	c.2365G>C	p.Ala789Pro	missense_variant	Exon 21 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.2389G>C	p.Ala797Pro	missense_variant	Exon 22 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.2365G>C	p.Ala789Pro	missense_variant	Exon 21 of 23	1		ENSP00000349635.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome Pathogenic:1

Jun 09, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine with proline at codon 797 of the OCRL protein (p.Ala797Pro). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and proline. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be hemizygous in individuals affected with Lowe syndrome (PMIID: 10923037, 21031565). This variant is also known as p.Ala780Pro in the literature. Experimental studies have shown that this missense change impairs binding to APPL1 and disrupts normal endosomal co-localization with EGFP (PMID: 17765681). In addition, experimental studies on fibroblasts from an individual carrying this missense change showed a reduced amount of OCRL protein and lower PI(4,5)P2-phosphatase activity (PMID: 21031565). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.50	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Pathogenic	0.84	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Benign	-0.48	T
MutationAssessor	Uncertain	2.5	M;.
PhyloP100		7.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.0	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0050	D;D
Sift4G	Uncertain	0.015	D;D
Polyphen		1.0	D;D
Vest4		0.90
MutPred		0.81		Gain of glycosylation at A797 (P = 0.0424);.;
MVP		0.84
MPC		1.8
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.99
gMVP		0.82
Mutation Taster		=10/90	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.44		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 10

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

Other links and lift over

dbSNP: rs935956958; hg19: chrX-128722910;