chrX-129544962-A-G

Variant names:

• chrX-129544962-A-G
• rs797045842
• NM_000276.4:c.124A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001318784.2(OCRL):​c.127A>G​(p.Ile43Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000965 in 1,036,007 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.7e-7 (0 hom. 0 hem.)
• Consequence: OCRL NM_001318784.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• Publications: 2 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: Ambry Genetics, G2P, Laboratory for Molecular Medicine, Orphanet, Labcorp Genetics (formerly Invitae)
• oculocerebrorenal syndrome

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

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=0.13427484).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001318784.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	NM_000276.4	MANE Select	c.124A>G	p.Ile42Val	missense	Exon 3 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.127A>G	p.Ile43Val	missense	Exon 3 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.124A>G	p.Ile42Val	missense	Exon 3 of 23	NP_001578.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.124A>G	p.Ile42Val	missense	Exon 3 of 24	ENSP00000360154.4
	OCRL	ENST00000357121.5	TSL:1	c.124A>G	p.Ile42Val	missense	Exon 3 of 23	ENSP00000349635.5
	OCRL	ENST00000949289.1		c.124A>G	p.Ile42Val	missense	Exon 3 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.65e-7 AC: 1 AN: 1036007 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 319049

African (AFR) AF: 0.00 AC: 0 AN: 25269

American (AMR) AF: 0.00 AC: 0 AN: 35143

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18972

East Asian (EAS) AF: 0.00 AC: 0 AN: 29909

South Asian (SAS) AF: 0.00 AC: 0 AN: 52755

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3967

European-Non Finnish (NFE) AF: 0.00000127 AC: 1 AN: 785808

Other (OTH) AF: 0.00 AC: 0 AN: 43978

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	18
DANN	Benign	0.95
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.70	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.13	T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	1.0	L
PhyloP100		1.5
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.16	N
REVEL	Benign	0.25
Sift	Benign	0.64	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.16
MVP		0.70
MPC		0.21
ClinPred		0.13	T
GERP RS		5.6
Varity_R		0.12
gMVP		0.30
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs797045842; hg19: chrX-128678939;