rs137853844

Variant names:

• chrX-129575956-C-A
• rs137853844
• NM_000276.4:c.1773C>A

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_000276.4(OCRL):​c.1773C>A​(p.Asn591Lys) 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 not provided (no stars).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 0.891
• Publications: 5 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: G2P, Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

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.1773C>A	p.Asn591Lys	missense	Exon 17 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.1776C>A	p.Asn592Lys	missense	Exon 17 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.1773C>A	p.Asn591Lys	missense	Exon 17 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.1773C>A	p.Asn591Lys	missense	Exon 17 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.1773C>A	p.Asn591Lys	missense	Exon 17 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.1770C>A	p.Asn590Lys	missense	Exon 17 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: not provided

Revision: no classification provided

Pathogenic	VUS	Benign	Condition
-	-	-	Lowe syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.89
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-4.5	D
REVEL	Pathogenic	0.86
Sift	Uncertain	0.0070	D
Sift4G	Uncertain	0.011	D
Polyphen		1.0	D
Vest4		0.89
MutPred		0.92		Gain of methylation at N591 (P = 0.0033)
MVP		0.99
MPC		2.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.85
gMVP		0.99
Mutation Taster		=11/89	disease causing

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

Other links and lift over

dbSNP: rs137853844; hg19: chrX-128709933;