X-129540488-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000276.4(OCRL):c.39+10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000203 in 1,147,905 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 43 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 15 hem., cov: 20)
  • Exomes 𝑓: 0.00011 (0 hom. 28 hem.)
• Consequence: OCRL NM_000276.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -1.63

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 Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.49).
• BP6: Variant X-129540488-G-A is Benign according to our data. Variant chrX-129540488-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193072.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00109 (117/106894) while in subpopulation AFR AF= 0.00379 (111/29318). AF 95% confidence interval is 0.00321. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 20. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OCRL	NM_000276.4	c.39+10G>A		intron_variant		ENST00000371113.9
OCRL	NM_001318784.2	c.39+10G>A		intron_variant
OCRL	NM_001587.4	c.39+10G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OCRL	ENST00000371113.9	c.39+10G>A		intron_variant		1	NM_000276.4	P1
OCRL	ENST00000357121.5	c.39+10G>A		intron_variant		1
OCRL	ENST00000691455.1	c.39+10G>A		intron_variant, NMD_transcript_variant
OCRL	ENST00000486673.1	n.91+549G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00109 AC: 117 AN: 106853 Hom.: 0 Cov.: 20 AF XY: 0.000511 AC XY: 15 AN XY: 29379

Gnomad AFR AF: 0.00379

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000195

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000392

Gnomad OTH AF: 0.00141

GnomAD3 exomes AF: 0.000337 AC: 32 AN: 95065 Hom.: 0 AF XY: 0.000202 AC XY: 7 AN XY: 34717

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000209

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000111 AC: 116 AN: 1041011 Hom.: 0 Cov.: 31 AF XY: 0.0000827 AC XY: 28 AN XY: 338469

Gnomad4 AFR exome AF: 0.00405

Gnomad4 AMR exome AF: 0.000216

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: 0.00000245

Gnomad4 OTH exome AF: 0.000182

GnomAD4 genome AF: 0.00109 AC: 117 AN: 106894 Hom.: 0 Cov.: 20 AF XY: 0.000510 AC XY: 15 AN XY: 29430

Gnomad4 AFR AF: 0.00379

Gnomad4 AMR AF: 0.000194

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000392

Gnomad4 OTH AF: 0.00139

Alfa AF: 0.000912 Hom.: 4

Bravo AF: 0.00143

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Feb 11, 2015

- -

Lowe syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Apr 20, 2022

- -

OCRL-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 17, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
Cadd	Benign	6.5
Dann	Benign	0.97

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

Publications

LitVar

Other links and lift over

dbSNP: rs765141317; hg19: chrX-128674465;