rs41303733

Variant names:

Variant summary

Our verdict is Benign. The variant received -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. 12/20 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

Publications

17 publications found

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 Gene-Disease associations (from GenCC):

X-linked intellectual disability-cerebellar hypoplasia syndrome
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

OPHN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 138573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 rank	MANE	Protein	UniProt
OPHN1	NM_002547.3 link	c.115G>A	p.Val39Ile	missense_variant	Exon 2 of 25	ENST00000355520.6	NP_002538.1	O60890-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6 link	c.115G>A	p.Val39Ile	missense_variant	Exon 2 of 25	1	NM_002547.3	ENSP00000347710.5		O60890-1

Frequencies

GnomAD3 genomes

AF:

0.0577

AC:

6494

AN:

112522

Hom.:

180

Cov.:

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

GnomAD2 exomes

AF:

0.0573

AC:

10488

AN:

183102

AF XY:

0.0566

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 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

African (AFR)

AF:

0.00993

AC:

262

AN:

26396

American (AMR)

AF:

0.0281

AC:

988

AN:

35199

Ashkenazi Jewish (ASJ)

AF:

0.0778

AC:

1508

AN:

19381

East Asian (EAS)

AF:

0.000166

AC:

AN:

30205

South Asian (SAS)

AF:

0.0252

AC:

1365

AN:

54139

European-Finnish (FIN)

AF:

0.0827

AC:

3346

AN:

40478

Middle Eastern (MID)

AF:

0.0708

AC:

293

AN:

4137

European-Non Finnish (NFE)

AF:

0.0859

AC:

72298

AN:

841794

Other (OTH)

AF:

0.0680

AC:

3133

AN:

46080

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

2784

5569

8353

11138

13922

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2614

5228

7842

10456

13070

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0577

AC:

6491

AN:

112574

Hom.:

180

Cov.:

AF XY:

0.0546

AC XY:

1895

AN XY:

34738

show subpopulations

African (AFR)

AF:

0.0104

AC:

323

AN:

31106

American (AMR)

AF:

0.0494

AC:

527

AN:

10672

Ashkenazi Jewish (ASJ)

AF:

0.0851

AC:

226

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.0198

AC:

AN:

2734

European-Finnish (FIN)

AF:

0.0746

AC:

459

AN:

6156

Middle Eastern (MID)

AF:

0.0930

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0872

AC:

4643

AN:

53253

Other (OTH)

AF:

0.0560

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

228

456

685

913

1141

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0736

Hom.:

4351

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

May 29, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

May 05, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Inborn genetic diseases

Benign:1

Dec 13, 2014

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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

PhyloP100

-0.15

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

PromoterAI

-0.12

Neutral

(source)

Varity_R

0.19

gMVP

0.65

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over