chrX-129557953-A-G

Variant names:

• chrX-129557953-A-G
• rs61752971
• NM_000276.4:c.439+3A>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PP3 BP6 BS1 BS2

The NM_000276.4(OCRL):​c.439+3A>G variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00334 in 1,136,037 control chromosomes in the GnomAD database, including 2 homozygotes. There are 1,075 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (0 hom., 60 hem., cov: 23)
  • Exomes 𝑓: 0.0034 (2 hom. 1015 hem.)
• Consequence: OCRL NM_000276.4 splice_region, intron
• Scores: Splicing: ADA: 0.9996
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:13
• Conservation: PhyloP100: 5.32
• Publications: 3 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 -8 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-129557953-A-G is Benign according to our data. Variant chrX-129557953-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 92725.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00245 (275/112228) while in subpopulation NFE AF = 0.00372 (198/53228). AF 95% confidence interval is 0.00329. There are 0 homozygotes in GnomAd4. There are 60 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Hemizygotes in GnomAd4 at 60 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.439+3A>G		splice_region intron	N/A	NP_000267.2
	OCRL	NM_001318784.2		c.442+3A>G		splice_region intron	N/A	NP_001305713.1
	OCRL	NM_001587.4		c.439+3A>G		splice_region intron	N/A	NP_001578.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OCRL	ENST00000371113.9	TSL:1 MANE Select	c.439+3A>G		splice_region intron	N/A	ENSP00000360154.4	Q01968-1
	OCRL	ENST00000357121.5	TSL:1	c.439+3A>G		splice_region intron	N/A	ENSP00000349635.5	Q01968-2
	OCRL	ENST00000949289.1		c.436+3A>G		splice_region intron	N/A	ENSP00000619348.1

Frequencies

GnomAD3 genomes AF: 0.00245 AC: 275 AN: 112177 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.000583

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00188

Gnomad ASJ AF: 0.00341

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000369

Gnomad FIN AF: 0.00378

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00372

Gnomad OTH AF: 0.00396

GnomAD2 exomes AF: 0.00240 AC: 440 AN: 183361 AF XY: 0.00265

Gnomad AFR exome AF: 0.000228

Gnomad AMR exome AF: 0.00106

Gnomad ASJ exome AF: 0.00214

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00375

Gnomad NFE exome AF: 0.00367

Gnomad OTH exome AF: 0.00309

GnomAD4 exome AF: 0.00344 AC: 3518 AN: 1023809 Hom.: 2 Cov.: 23 AF XY: 0.00337 AC XY: 1015 AN XY: 301535

African (AFR) AF: 0.000440 AC: 11 AN: 25024

American (AMR) AF: 0.00102 AC: 36 AN: 35134

Ashkenazi Jewish (ASJ) AF: 0.00201 AC: 38 AN: 18941

East Asian (EAS) AF: 0.00 AC: 0 AN: 29935

South Asian (SAS) AF: 0.00126 AC: 66 AN: 52516

European-Finnish (FIN) AF: 0.00444 AC: 180 AN: 40506

Middle Eastern (MID) AF: 0.00151 AC: 6 AN: 3961

European-Non Finnish (NFE) AF: 0.00397 AC: 3076 AN: 774063

Other (OTH) AF: 0.00240 AC: 105 AN: 43729

GnomAD4 genome AF: 0.00245 AC: 275 AN: 112228 Hom.: 0 Cov.: 23 AF XY: 0.00174 AC XY: 60 AN XY: 34398

African (AFR) AF: 0.000582 AC: 18 AN: 30940

American (AMR) AF: 0.00188 AC: 20 AN: 10625

Ashkenazi Jewish (ASJ) AF: 0.00341 AC: 9 AN: 2642

East Asian (EAS) AF: 0.00 AC: 0 AN: 3568

South Asian (SAS) AF: 0.000370 AC: 1 AN: 2701

European-Finnish (FIN) AF: 0.00378 AC: 23 AN: 6087

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 217

European-Non Finnish (NFE) AF: 0.00372 AC: 198 AN: 53228

Other (OTH) AF: 0.00391 AC: 6 AN: 1535

Alfa AF: 0.00171 Hom.: 26

Bravo AF: 0.00196

EpiCase AF: 0.00360

EpiControl AF: 0.00344

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	5	not provided (6)
-	-	3	not specified (3)
-	-	2	Lowe syndrome (2)
-	1	-	Developmental cataract (1)
-	-	1	Epilepsy (1)
-	1	-	Genetic developmental and epileptic encephalopathy (1)
-	-	1	Lowe syndrome;C1845167:Dent disease type 2 (1)
-	-	1	Nephrolithiasis/nephrocalcinosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	19
DANN	Benign	0.96
PhyloP100		5.3
Mutation Taster		=20/80	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.97
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -3

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

Other links and lift over

dbSNP: rs61752971; hg19: chrX-128691930;