rs148208753

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_ModerateBP6_Very_StrongBS2

The NM_002547.3(OPHN1):c.2362C>T(p.Arg788Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,204,966 control chromosomes in the GnomAD database, including 1 homozygotes. There are 48 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.00012 ( 1 hom. 45 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 1.92

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.077751756).

BP6

Variant X-68052553-G-A is Benign according to our data. Variant chrX-68052553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 378314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68052553-G-A is described in Lovd as [Likely_benign].

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPHN1	NM_002547.3 linkuse as main transcript	c.2362C>T	p.Arg788Trp	missense_variant	23/25	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6 linkuse as main transcript	c.2362C>T	p.Arg788Trp	missense_variant	23/25	1	NM_002547.3	ENSP00000347710	P1	O60890-1

Frequencies

GnomAD3 genomes

AF:

0.000161

AC:

AN:

111815

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

34021

show subpopulations

Gnomad AFR

AF:

0.000163

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

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:

0.000207

Gnomad OTH

AF:

0.000667

GnomAD3 exomes

AF:

0.000240

AC:

AN:

170737

Hom.:

AF XY:

0.000246

AC XY:

AN XY:

56881

show subpopulations

Gnomad AFR exome

AF:

0.000243

Gnomad AMR exome

AF:

0.000604

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000757

Gnomad SAS exome

AF:

0.0000584

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000201

Gnomad OTH exome

AF:

0.00117

GnomAD4 exome

AF:

0.000121

AC:

132

AN:

1093151

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

359309

show subpopulations

Gnomad4 AFR exome

AF:

0.000569

Gnomad4 AMR exome

AF:

0.000519

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000566

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000810

Gnomad4 OTH exome

AF:

0.000414

GnomAD4 genome

AF:

0.000161

AC:

AN:

111815

Hom.:

Cov.:

AF XY:

0.0000882

AC XY:

AN XY:

34021

show subpopulations

Gnomad4 AFR

AF:

0.000163

Gnomad4 AMR

AF:

0.0000945

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000207

Gnomad4 OTH

AF:

0.000667

Alfa

AF:

0.000141

Hom.:

Bravo

AF:

0.000181

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000289

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 16, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	This variant is associated with the following publications: (PMID: 23552953) -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	OPHN1: PM5, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 23, 2018

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2017

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. -

X-linked intellectual disability-cerebellar hypoplasia syndrome

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

OPHN1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2021

This variant is classified as likely 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

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.50

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.31

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.082

MetaRNN

Benign

0.078

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

MutationTaster

Benign

1.0

D;N

PrimateAI

Uncertain

0.78

PROVEAN

Uncertain

-2.8

REVEL

Benign

0.19

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0080

Polyphen

1.0

Vest4

0.17

MVP

0.37

MPC

0.41

ClinPred

0.084

GERP RS

2.0

Varity_R

0.21

gMVP

0.42

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

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