X-129540464-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000276.4(OCRL):c.25G>A(p.Ala9Thr) 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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A9A) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 21)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.10

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.18408066).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.25G>A	p.Ala9Thr	missense_variant	1/24	ENST00000371113.9
OCRL	NM_001318784.2	c.25G>A	p.Ala9Thr	missense_variant	1/24
OCRL	NM_001587.4	c.25G>A	p.Ala9Thr	missense_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.25G>A	p.Ala9Thr	missense_variant	1/24	1	NM_000276.4	P1
OCRL	ENST00000357121.5	c.25G>A	p.Ala9Thr	missense_variant	1/23	1
OCRL	ENST00000691455.1	c.25G>A	p.Ala9Thr	missense_variant, NMD_transcript_variant	1/18
OCRL	ENST00000486673.1	n.91+525G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 21

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 17, 2017

The A9T variant in the OCRL gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The A9T variant is not observed in large population cohorts; however, limited data are available (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The A9T variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is not conserved. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret A9T as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.62	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.92	N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.16
Sift	Benign	0.17	T;T
Sift4G	Benign	0.60	T;T
Polyphen		0.067	B;B
Vest4		0.092
MutPred		0.14		Gain of relative solvent accessibility (P = 0.0082);Gain of relative solvent accessibility (P = 0.0082);
MVP		0.56
MPC		0.25
ClinPred		0.14	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.065
gMVP		0.23

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: rs1064796554; hg19: chrX-128674441;