rs137853829

Variant names:

• chrX-129560648-T-C
• rs137853829
• NM_000276.4:c.821T>C

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.821T>C​(p.Ile274Thr) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 7.67

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, 0.98
• PP5: Variant X-129560648-T-C is Pathogenic according to our data. Variant chrX-129560648-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 68724.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-129560648-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OCRL	NM_000276.4	c.821T>C	p.Ile274Thr	missense_variant	Exon 9 of 24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.824T>C	p.Ile275Thr	missense_variant	Exon 9 of 24		NP_001305713.1
OCRL	NM_001587.4	c.821T>C	p.Ile274Thr	missense_variant	Exon 9 of 23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.821T>C	p.Ile274Thr	missense_variant	Exon 9 of 24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.821T>C	p.Ile274Thr	missense_variant	Exon 9 of 23	1		ENSP00000349635.5

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 21

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome;C1845167:Dent disease type 2 Pathogenic:1

Jan 29, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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	Uncertain	0.51
BayesDel_addAF	Pathogenic	0.70	D
BayesDel_noAF	Pathogenic	0.77
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.90	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.7	H;H
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Pathogenic	0.95
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.98	D;P
Vest4		0.75
MutPred		0.88		Loss of stability (P = 0.031);Loss of stability (P = 0.031);
MVP		1.0
MPC		1.6
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs137853829; hg19: chrX-128694625;