rs1182741031

Variant names:

• chrX-129575158-C-T
• rs1182741031
• NM_000276.4:c.1621C>T
• OCRL p.Arg541*

Your query was ambiguous. Multiple possible variants found:

• chrX-129575158-C-T
• chrX-129575158-C-A
• chrX-129575158-C-G

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000276.4(OCRL):​c.1621C>T​(p.Arg541*) variant causes a stop gained 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 (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.06
• Publications: 1 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: Orphanet, Laboratory for Molecular Medicine, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-129575158-C-T is Pathogenic according to our data. Variant chrX-129575158-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 521093.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000276.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	NM_000276.4	MANE Select	c.1621C>T	p.Arg541*	stop_gained	Exon 16 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.1624C>T	p.Arg542*	stop_gained	Exon 16 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.1621C>T	p.Arg541*	stop_gained	Exon 16 of 23	NP_001578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.1621C>T	p.Arg541*	stop_gained	Exon 16 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.1621C>T	p.Arg541*	stop_gained	Exon 16 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.1618C>T	p.Arg540*	stop_gained	Exon 16 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	Lowe syndrome (4)
2	-	-	not provided (2)
1	-	-	Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.95	D
PhyloP100		3.1
Mutation Taster		=4/196	disease causing (ClinVar)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1182741031;

hg19: chrX-128709135;

COSMIC: COSV63980851;