chrX-129540456-C-G

Variant names:

• chrX-129540456-C-G
• rs759203987
• NM_000276.4:c.17C>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4 BP6_Moderate BS2

The NM_000276.4(OCRL):​c.17C>G​(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000138 in 1,016,230 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 5 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 0.000014 (0 hom. 5 hem.)
• Consequence: OCRL NM_000276.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.17
• 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: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37938103).
• BP6: Variant X-129540456-C-G is Benign according to our data. Variant chrX-129540456-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2082205.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Hemizygotes in GnomAdExome4 at 5 XL gene

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.17C>G	p.Pro6Arg	missense	Exon 1 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.17C>G	p.Pro6Arg	missense	Exon 1 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.17C>G	p.Pro6Arg	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.17C>G	p.Pro6Arg	missense	Exon 1 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.17C>G	p.Pro6Arg	missense	Exon 1 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.17C>G	p.Pro6Arg	missense	Exon 1 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD2 exomes AF: 0.0000105 AC: 1 AN: 95693 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000130

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000138 AC: 14 AN: 1016230 Hom.: 0 Cov.: 31 AF XY: 0.0000153 AC XY: 5 AN XY: 326540

African (AFR) AF: 0.00 AC: 0 AN: 23875

American (AMR) AF: 0.0000371 AC: 1 AN: 26929

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17502

East Asian (EAS) AF: 0.00 AC: 0 AN: 25019

South Asian (SAS) AF: 0.0000202 AC: 1 AN: 49483

European-Finnish (FIN) AF: 0.0000366 AC: 1 AN: 27297

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2768

European-Non Finnish (NFE) AF: 0.0000125 AC: 10 AN: 801098

Other (OTH) AF: 0.0000237 AC: 1 AN: 42259

GnomAD4 genome Cov.: 20

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Lowe syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.26	T
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.98	D
MetaRNN	Benign	0.38	T
MetaSVM	Uncertain	0.24	D
MutationAssessor	Benign	1.4	L
PhyloP100		3.2
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.37	N
REVEL	Uncertain	0.29
Sift	Uncertain	0.028	D
Sift4G	Benign	0.21	T
Polyphen		0.48	P
Vest4		0.39
MutPred		0.18		Gain of sheet (P = 0.0507)
MVP		0.80
MPC		0.49
ClinPred		0.28	T
GERP RS		3.9
PromoterAI		-0.019	Neutral
Varity_R		0.12
gMVP		0.37
Mutation Taster		=89/11	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: rs759203987; hg19: chrX-128674433;