X-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 (no stars). 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 no assertion criteria provided U:1
• 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]

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	UniProt
OCRL	NM_000276.4	c.19G>T	p.Val7Phe	missense_variant	1/24	ENST00000371113.9
OCRL	NM_001318784.2	c.19G>T	p.Val7Phe	missense_variant	1/24
OCRL	NM_001587.4	c.19G>T	p.Val7Phe	missense_variant	1/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.19G>T	p.Val7Phe	missense_variant	1/24	1	NM_000276.4	P1
OCRL	ENST00000357121.5	c.19G>T	p.Val7Phe	missense_variant	1/23	1
OCRL	ENST00000691455.1	c.19G>T	p.Val7Phe	missense_variant, NMD_transcript_variant	1/18
OCRL	ENST00000486673.1	n.91+519G>T		intron_variant, non_coding_transcript_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:1

Revision: no assertion criteria provided

Submissions by phenotype

Intellectual disability Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

New York Genome Center

Jan 16, 2020

- -

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
MutationTaster	Benign	1.0	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;