rs137853848

Variant names:

• chrX-129562665-C-T
• rs137853848
• NM_000276.4:c.1123C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000276.4(OCRL):​c.1123C>T​(p.His375Tyr) 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 not provided (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H375R) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 22)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 7.57
• Publications: 2 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-129562666-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373191.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.1123C>T	p.His375Tyr	missense_variant	Exon 12 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.1126C>T	p.His376Tyr	missense_variant	Exon 12 of 24		NP_001305713.1
OCRL	NM_001587.4	c.1123C>T	p.His375Tyr	missense_variant	Exon 12 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.1123C>T	p.His375Tyr	missense_variant	Exon 12 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.1123C>T	p.His375Tyr	missense_variant	Exon 12 of 23	1		ENSP00000349635.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

Lowe syndrome Other:1

-

UniProtKB/Swiss-Prot

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.73	D
BayesDel_noAF	Pathogenic	0.81
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	3.6	H;H
PhyloP100		7.6
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-6.0	D;D
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.94
MutPred		0.95		Loss of disorder (P = 0.0721);Loss of disorder (P = 0.0721);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.99
gMVP		0.99
Mutation Taster		=6/94	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs137853848; hg19: chrX-128696642;