rs61752970

Variant names:

• chrX-129540745-C-T
• rs61752970
• NM_000276.4:c.41C>T
• OCRL p.Thr14Ile

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000276.4(OCRL):​c.41C>T​(p.Thr14Ile) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00689 in 1,205,712 control chromosomes in the GnomAD database, including 23 homozygotes. There are 2,616 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. 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. T14A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., 148 hem., cov: 22)
  • Exomes 𝑓: 0.0071 (21 hom. 2468 hem.)
• Consequence: OCRL NM_000276.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 2.14
• Publications: 8 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, Laboratory for Molecular Medicine, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• oculocerebrorenal syndrome

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047611).
• BP6: Variant X-129540745-C-T is Benign according to our data. Variant chrX-129540745-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 129850.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00482 (534/110820) while in subpopulation NFE AF = 0.00746 (393/52690). AF 95% confidence interval is 0.00685. There are 2 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.41C>T	p.Thr14Ile	missense splice_region	Exon 2 of 24	NP_000267.2
	OCRL	NM_001318784.2		c.44C>T	p.Thr15Ile	missense	Exon 2 of 24	NP_001305713.1
	OCRL	NM_001587.4		c.41C>T	p.Thr14Ile	missense splice_region	Exon 2 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.41C>T	p.Thr14Ile	missense splice_region	Exon 2 of 24	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.41C>T	p.Thr14Ile	missense splice_region	Exon 2 of 23	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.41C>T	p.Thr14Ile	missense splice_region	Exon 2 of 24	ENSP00000619348.1

Frequencies

GnomAD3 genomes AF: 0.00482 AC: 534 AN: 110771 Hom.: 2 Cov.: 22

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.000760

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00116

Gnomad FIN AF: 0.0131

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00746

Gnomad OTH AF: 0.00201

GnomAD2 exomes AF: 0.00565 AC: 1036 AN: 183264 AF XY: 0.00612

Gnomad AFR exome AF: 0.000989

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0179

Gnomad NFE exome AF: 0.00760

Gnomad OTH exome AF: 0.00575

GnomAD4 exome AF: 0.00710 AC: 7775 AN: 1094892 Hom.: 21 Cov.: 30 AF XY: 0.00685 AC XY: 2468 AN XY: 360456

African (AFR) AF: 0.000722 AC: 19 AN: 26332

American (AMR) AF: 0.00202 AC: 71 AN: 35200

Ashkenazi Jewish (ASJ) AF: 0.00119 AC: 23 AN: 19368

East Asian (EAS) AF: 0.00 AC: 0 AN: 30192

South Asian (SAS) AF: 0.00174 AC: 94 AN: 54061

European-Finnish (FIN) AF: 0.0172 AC: 698 AN: 40518

Middle Eastern (MID) AF: 0.000977 AC: 4 AN: 4096

European-Non Finnish (NFE) AF: 0.00789 AC: 6621 AN: 839140

Other (OTH) AF: 0.00533 AC: 245 AN: 45985

GnomAD4 genome AF: 0.00482 AC: 534 AN: 110820 Hom.: 2 Cov.: 22 AF XY: 0.00448 AC XY: 148 AN XY: 33034

African (AFR) AF: 0.00121 AC: 37 AN: 30552

American (AMR) AF: 0.00170 AC: 18 AN: 10568

Ashkenazi Jewish (ASJ) AF: 0.000760 AC: 2 AN: 2632

East Asian (EAS) AF: 0.00 AC: 0 AN: 3445

South Asian (SAS) AF: 0.00116 AC: 3 AN: 2588

European-Finnish (FIN) AF: 0.0131 AC: 78 AN: 5950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 213

European-Non Finnish (NFE) AF: 0.00746 AC: 393 AN: 52690

Other (OTH) AF: 0.00198 AC: 3 AN: 1515

Alfa AF: 0.00615 Hom.: 282

Bravo AF: 0.00396

EpiCase AF: 0.00654

EpiControl AF: 0.00865

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	4	not specified (4)
-	-	1	Lowe syndrome (1)
-	-	1	Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.41	T
MetaRNN	Benign	0.0048	T
MetaSVM	Uncertain	-0.013	T
MutationAssessor	Benign	1.0	L
PhyloP100		2.1
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.23
Sift	Uncertain	0.018	D
Sift4G	Benign	0.34	T
PromoterAI		0.10	Neutral
Varity_R		0.061
gMVP		0.68
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs61752970;

hg19: chrX-128674722;

COSMIC: COSV105254410;

COSMIC: COSV105254410;