X-129540458-G-T

Position:

• chrX-129540458-G-T

Variant summary

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

The NM_000276.4(OCRL):​c.19G>T​(p.Val7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000192 in 1,043,932 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. 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: 0.0000019 (0 hom. 1 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0940

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 (HGNC:):

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=0.22404447).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCRL	NM_000276.4	c.19G>T	p.Val7Phe	missense_variant	1/24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.19G>T	p.Val7Phe	missense_variant	1/24		NP_001305713.1
OCRL	NM_001587.4	c.19G>T	p.Val7Phe	missense_variant	1/23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.19G>T	p.Val7Phe	missense_variant	1/24	1	NM_000276.4	ENSP00000360154.4
OCRL	ENST00000357121.5	c.19G>T	p.Val7Phe	missense_variant	1/23	1		ENSP00000349635.5
OCRL	ENST00000691455.1	n.19G>T		non_coding_transcript_exon_variant	1/18			ENSP00000510265.1
OCRL	ENST00000486673.1	n.91+519G>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 0.00000192 AC: 2 AN: 1043932 Hom.: 0 Cov.: 31 AF XY: 0.00000293 AC XY: 1 AN XY: 341226

Gnomad4 AFR exome AF: 0.0000404

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: 0.00000122

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Lowe syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

Jan 07, 2022

- -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T;.
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.74	T;T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N;N
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.42	N;N
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D;D
Sift4G	Benign	0.17	T;T
Polyphen		0.0	B;B
Vest4		0.31
MutPred		0.12		Gain of glycosylation at P6 (P = 0.0953);Gain of glycosylation at P6 (P = 0.0953);
MVP		0.76
MPC		0.34
ClinPred		0.089	T
GERP RS		-1.6
Varity_R		0.084
gMVP		0.39

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: rs1935772672; hg19: chrX-128674435;