X-129540468-A-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BP4

The NM_000276.4(OCRL):c.29A>T(p.Gln10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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_benign. Variant got -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31008816).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.29A>T	p.Gln10Leu	missense_variant	1/24	ENST00000371113.9
OCRL	NM_001318784.2	c.29A>T	p.Gln10Leu	missense_variant	1/24
OCRL	NM_001587.4	c.29A>T	p.Gln10Leu	missense_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.29A>T	p.Gln10Leu	missense_variant	1/24	1	NM_000276.4	P1
OCRL	ENST00000357121.5	c.29A>T	p.Gln10Leu	missense_variant	1/23	1
OCRL	ENST00000691455.1	c.29A>T	p.Gln10Leu	missense_variant, NMD_transcript_variant	1/18
OCRL	ENST00000486673.1	n.91+529A>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1019985 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 328261

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 22, 2023

This sequence change replaces glutamine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 10 of the OCRL protein (p.Gln10Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with OCRL-related conditions. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt OCRL protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.30	T;.
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.68	T;T
M_CAP	Pathogenic	0.99	D
MetaRNN	Benign	0.31	T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.98	D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.3	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0030	D;D
Sift4G	Benign	0.42	T;T
Polyphen		0.037	B;B
Vest4		0.35
MutPred		0.24		Loss of sheet (P = 0.0457);Loss of sheet (P = 0.0457);
MVP		0.93
MPC		0.26
ClinPred		0.32	T
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
gMVP		0.40

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs924766896; hg19: chrX-128674445;