NM_000276.4:c.19G>T

Variant names:

• chrX-129540458-G-T
• rs1935772672
• NM_000276.4:c.19G>T

Variant summary

Our verdict is Uncertain significance. The variant received 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 (★★). Synonymous variant affecting the same amino acid position (i.e. V7V) has been classified as Likely benign.

• 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
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Dent disease type 2

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22404447).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000276.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	NM_000276.4	MANE Select	c.19G>T	p.Val7Phe	missense	Exon 1 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.19G>T	p.Val7Phe	missense	Exon 1 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.19G>T	p.Val7Phe	missense	Exon 1 of 23	NP_001578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.19G>T	p.Val7Phe	missense	Exon 1 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.19G>T	p.Val7Phe	missense	Exon 1 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.19G>T	p.Val7Phe	missense	Exon 1 of 24	ENSP00000619348.1

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

African (AFR) AF: 0.0000404 AC: 1 AN: 24774

American (AMR) AF: 0.00 AC: 0 AN: 27860

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18576

East Asian (EAS) AF: 0.00 AC: 0 AN: 27077

South Asian (SAS) AF: 0.00 AC: 0 AN: 49779

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2932

European-Non Finnish (NFE) AF: 0.00000122 AC: 1 AN: 818798

Other (OTH) AF: 0.00 AC: 0 AN: 44144

GnomAD4 genome Cov.: 20

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Lowe syndrome (1)
-	1	-	Lowe syndrome;C1845167:Dent disease type 2 (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.094
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.42	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.013	D
Sift4G	Benign	0.17	T
Polyphen		0.0	B
Vest4		0.31
MutPred		0.12		Gain of glycosylation at P6 (P = 0.0953)
MVP		0.76
MPC		0.34
ClinPred		0.089	T
GERP RS		-1.6
PromoterAI		-0.058	Neutral
Varity_R		0.084
gMVP		0.39
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs1935772672; hg19: chrX-128674435;