rs41303733

Positions:

chrX-68432906-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002547.3(OPHN1):c.115G>A(p.Val39Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0741 in 1,210,383 control chromosomes in the GnomAD database, including 2,555 homozygotes. There are 28,778 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.058 ( 180 hom., 1895 hem., cov: 24)

Exomes 𝑓: 0.076 ( 2375 hom. 26883 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.148

Variant links:

Genes affected

OPHN1 (HGNC:8148): (oligophrenin 1) This gene encodes a Rho-GTPase-activating protein that promotes GTP hydrolysis of Rho subfamily members. Rho proteins are important mediators of intracellular signal transduction, which affects cell migration and cell morphogenesis. Mutations in this gene are responsible for OPHN1-related X-linked cognitive disability with cerebellar hypoplasia and distinctive facial dysmorhphism. [provided by RefSeq, Jul 2008]

OPHN1 links:

OPHN1 (HGNC:):

OPHN1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0017223358).

BP6

Variant X-68432906-C-T is Benign according to our data. Variant chrX-68432906-C-T is described in ClinVar as [Benign]. Clinvar id is 138573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68432906-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0851 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPHN1	NM_002547.3 linkuse as main transcript	c.115G>A	p.Val39Ile	missense_variant	2/25	ENST00000355520.6	NP_002538.1	O60890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6 linkuse as main transcript	c.115G>A	p.Val39Ile	missense_variant	2/25	1	NM_002547.3	ENSP00000347710.5		O60890-1

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

6494

AN:

112522

Hom.:

180

Cov.:

AF XY:

0.0546

AC XY:

1893

AN XY:

34676

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.225

Gnomad AMR

AF:

0.0495

Gnomad ASJ

AF:

0.0851

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0193

Gnomad FIN

AF:

0.0746

Gnomad MID

AF:

0.0928

Gnomad NFE

AF:

0.0872

Gnomad OTH

AF:

0.0567

GnomAD3 exomes

AF:

0.0573

AC:

10488

AN:

183102

Hom.:

259

AF XY:

0.0566

AC XY:

3823

AN XY:

67550

show subpopulations

Gnomad AFR exome

AF:

0.00988

Gnomad AMR exome

AF:

0.0268

Gnomad ASJ exome

AF:

0.0817

Gnomad EAS exome

AF:

0.0000722

Gnomad SAS exome

AF:

0.0253

Gnomad FIN exome

AF:

0.0787

Gnomad NFE exome

AF:

0.0852

Gnomad OTH exome

AF:

0.0692

GnomAD4 exome

AF:

0.0758

AC:

83198

AN:

1097809

Hom.:

2375

Cov.:

AF XY:

0.0740

AC XY:

26883

AN XY:

363205

show subpopulations

Gnomad4 AFR exome

AF:

0.00993

Gnomad4 AMR exome

AF:

0.0281

Gnomad4 ASJ exome

AF:

0.0778

Gnomad4 EAS exome

AF:

0.000166

Gnomad4 SAS exome

AF:

0.0252

Gnomad4 FIN exome

AF:

0.0827

Gnomad4 NFE exome

AF:

0.0859

Gnomad4 OTH exome

AF:

0.0680

GnomAD4 genome

AF:

0.0577

AC:

6491

AN:

112574

Hom.:

180

Cov.:

AF XY:

0.0546

AC XY:

1895

AN XY:

34738

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0494

Gnomad4 ASJ

AF:

0.0851

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0198

Gnomad4 FIN

AF:

0.0746

Gnomad4 NFE

AF:

0.0872

Gnomad4 OTH

AF:

0.0560

Alfa

AF:

0.0791

Hom.:

3840

Bravo

AF:

0.0539

TwinsUK

AF:

0.0817

AC:

303

ALSPAC

AF:

0.0817

AC:

236

ESP6500AA

AF:

0.0146

AC:

ESP6500EA

AF:

0.0782

AC:

526

ExAC

AF:

0.0595

AC:

7219

EpiCase

AF:

0.0861

EpiControl

AF:

0.0838

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 29, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 05, 2018	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2014

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.85

BayesDel_noAF

Benign

-0.92

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.026

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.71

MetaRNN

Benign

0.0017

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.82

PrimateAI

Uncertain

0.54

PROVEAN

Benign

0.51

REVEL

Benign

0.10

Sift

Benign

0.27

Sift4G

Uncertain

0.044

Polyphen

0.84

Vest4

0.081

MPC

0.94

ClinPred

0.025

GERP RS

4.6

Varity_R

0.19

gMVP

0.65

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over