rs935956958

chrX-129588933-G-CchrX-129588933-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 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 id is 567454.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.2389G>C	p.Ala797Pro	missense_variant	22/24	ENST00000371113.9
OCRL	NM_001318784.2	c.2392G>C	p.Ala798Pro	missense_variant	22/24
OCRL	NM_001587.4	c.2365G>C	p.Ala789Pro	missense_variant	21/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.2389G>C	p.Ala797Pro	missense_variant	22/24	1	NM_000276.4	P1

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

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jun 09, 2018

For these reasons, this variant has been classified as Pathogenic. 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). 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. This variant is not present in population databases (ExAC no frequency). 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. -

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;.
MutationTaster	Benign	1.0	D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs935956958; hg19: chrX-128722910;