rs137853262

chrX-129567333-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_000276.4(OCRL):c.1436A>G(p.Tyr479Cys) variant causes a missense change involving the alteration of a non-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 (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1 O:1
• Conservation: PhyloP100: 3.29

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.975
• PP5: Variant X-129567333-A-G is Pathogenic according to our data. Variant chrX-129567333-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 10860.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.1436A>G	p.Tyr479Cys	missense_variant	14/24	ENST00000371113.9
OCRL	NM_001318784.2	c.1439A>G	p.Tyr480Cys	missense_variant	14/24
OCRL	NM_001587.4	c.1436A>G	p.Tyr479Cys	missense_variant	14/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.1436A>G	p.Tyr479Cys	missense_variant	14/24	1	NM_000276.4	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Dent disease type 2 Pathogenic:1 Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 22, 2021	- -
not provided, no classification provided	literature only	UniProtKB/Swiss-Prot	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.72
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D;.
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.9	H;H
MutationTaster	Benign	1.0	A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.2	D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.85		Loss of ubiquitination at K478 (P = 0.0638);Loss of ubiquitination at K478 (P = 0.0638);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.97
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853262; hg19: chrX-128701310;