OCRL p.Met299Ile

Variant names:

• chrX-129561251-G-T
• NM_000276.4:c.897G>T
• OCRL p.Met299Ile

Your query was ambiguous. Multiple possible variants found:

• chrX-129561251-G-T
• chrX-129561251-G-C
• chrX-129561251-G-A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000276.4(OCRL):​c.897G>T​(p.Met299Ile) 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 benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M299V) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00900
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122700125).

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.897G>T	p.Met299Ile	missense	Exon 10 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.900G>T	p.Met300Ile	missense	Exon 10 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.897G>T	p.Met299Ile	missense	Exon 10 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.897G>T	p.Met299Ile	missense	Exon 10 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.897G>T	p.Met299Ile	missense	Exon 10 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.894G>T	p.Met298Ile	missense	Exon 10 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	17
DANN	Benign	0.96
DEOGEN2	Uncertain	0.57	D
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.43	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	-0.73	N
PhyloP100		-0.0090
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.13
Sift	Benign	0.057	T
Sift4G	Uncertain	0.047	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.61
Mutation Taster		=99/1	polymorphism

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

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

Other links and lift over

hg19: chrX-128695228;