X-129540456-C-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4 BP6_Moderate

The NM_000276.4(OCRL):c.17C>G(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,016,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.17

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 -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37938103).
• BP6: Variant X-129540456-C-G is Benign according to our data. Variant chrX-129540456-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2082205.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.17C>G	p.Pro6Arg	missense_variant	1/24	ENST00000371113.9
OCRL	NM_001318784.2	c.17C>G	p.Pro6Arg	missense_variant	1/24
OCRL	NM_001587.4	c.17C>G	p.Pro6Arg	missense_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.17C>G	p.Pro6Arg	missense_variant	1/24	1	NM_000276.4	P1
OCRL	ENST00000357121.5	c.17C>G	p.Pro6Arg	missense_variant	1/23	1
OCRL	ENST00000691455.1	c.17C>G	p.Pro6Arg	missense_variant, NMD_transcript_variant	1/18
OCRL	ENST00000486673.1	n.91+517C>G		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.0000105 AC: 1 AN: 95693 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 35065

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000130

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 14 AN: 1016230 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 5 AN XY: 326540

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000371

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000202

Gnomad4 FIN exome AF: 0.0000366

Gnomad4 NFE exome AF: 0.0000125

Gnomad4 OTH exome AF: 0.0000237

GnomAD4 genome Cov.: 20

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lowe syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Benign	0.26	T;.
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.74	N;N
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.37	N;N
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D;D
Sift4G	Benign	0.21	T;T
Polyphen		0.48	P;D
Vest4		0.39
MutPred		0.18		Gain of sheet (P = 0.0507);Gain of sheet (P = 0.0507);
MVP		0.80
MPC		0.49
ClinPred		0.28	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs759203987; hg19: chrX-128674433;