X-129588933-G-T

Position:

• chrX-129588933-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_000276.4(OCRL):​c.2389G>T​(p.Ala797Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000891 in 112,175 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000089 (0 hom., 1 hem., cov: 23)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OCRL	NM_000276.4	c.2389G>T	p.Ala797Ser	missense_variant	22/24	ENST00000371113.9	NP_000267.2
OCRL	NM_001318784.2	c.2392G>T	p.Ala798Ser	missense_variant	22/24		NP_001305713.1
OCRL	NM_001587.4	c.2365G>T	p.Ala789Ser	missense_variant	21/23		NP_001578.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OCRL	ENST00000371113.9	c.2389G>T	p.Ala797Ser	missense_variant	22/24	1	NM_000276.4	ENSP00000360154	P1

Frequencies

GnomAD3 genomes AF: 0.00000891 AC: 1 AN: 112175 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34329

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome AF: 0.00000891 AC: 1 AN: 112175 Hom.: 0 Cov.: 23 AF XY: 0.0000291 AC XY: 1 AN XY: 34329

Gnomad4 AFR AF: 0.0000324

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.72	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.97	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.11	N;N
REVEL	Benign	0.20
Sift	Benign	0.73	T;T
Sift4G	Benign	0.94	T;T
Polyphen		0.56	P;D
Vest4		0.27
MutPred		0.54		Gain of relative solvent accessibility (P = 0.1894);.;
MVP		0.84
MPC		1.5
ClinPred		0.90	D
GERP RS		5.8
Varity_R		0.59
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.58		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.58		Position offset: 10

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs935956958; hg19: chrX-128722910;