rs36095561

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_002547.3(OPHN1):c.2079G>A(p.Met693Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000705 in 1,199,775 control chromosomes in the GnomAD database, including 4 homozygotes. There are 210 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., 91 hem., cov: 22)

Exomes 𝑓: 0.00041 ( 2 hom. 119 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.00700

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 -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0025024414).

BP6

Variant X-68063933-C-T is Benign according to our data. Variant chrX-68063933-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 159475.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3 linkuse as main transcript	c.2079G>A	p.Met693Ile	missense_variant	21/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6 linkuse as main transcript	c.2079G>A	p.Met693Ile	missense_variant	21/25	1	NM_002547.3	P1	O60890-1

Frequencies

GnomAD3 genomes

AF:

0.00361

AC:

399

AN:

110442

Hom.:

Cov.:

AF XY:

0.00279

AC XY:

AN XY:

32660

show subpopulations

Gnomad AFR

AF:

0.0128

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

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:

0.00

Gnomad OTH

AF:

0.00135

GnomAD3 exomes

AF:

0.00112

AC:

191

AN:

170737

Hom.:

AF XY:

0.000834

AC XY:

AN XY:

56337

show subpopulations

Gnomad AFR exome

AF:

0.0139

Gnomad AMR exome

AF:

0.000424

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000607

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000131

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000410

AC:

447

AN:

1089281

Hom.:

Cov.:

AF XY:

0.000334

AC XY:

119

AN XY:

355889

show subpopulations

Gnomad4 AFR exome

AF:

0.0132

Gnomad4 AMR exome

AF:

0.000607

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000569

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000251

Gnomad4 OTH exome

AF:

0.00107

GnomAD4 genome

AF:

0.00361

AC:

399

AN:

110494

Hom.:

Cov.:

AF XY:

0.00278

AC XY:

AN XY:

32722

show subpopulations

Gnomad4 AFR

AF:

0.0127

Gnomad4 AMR

AF:

0.00105

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00133

Alfa

AF:

0.00104

Hom.:

Bravo

AF:

0.00433

ESP6500AA

AF:

0.0130

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00126

AC:

153

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 22, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 03, 2017	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 01, 2016

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 17, 2021

- -

OPHN1-related disorder

Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 13, 2019

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

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.88

BayesDel_noAF

Benign

-1.0

Cadd

Benign

4.7

Dann

Benign

0.78

DEOGEN2

Benign

0.060

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0025

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.69

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.30

REVEL

Benign

0.045

Sift

Benign

0.46

Sift4G

Benign

0.47

Polyphen

0.0

Vest4

0.16

MutPred

0.099

Gain of catalytic residue at M693 (P = 0.0267);

MVP

0.12

MPC

0.13

ClinPred

0.0017

GERP RS

1.2

Varity_R

0.081

gMVP

0.055

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