chrX-68206604-G-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002547.3(OPHN1):c.902C>T(p.Thr301Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00144 in 1,208,730 control chromosomes in the GnomAD database, including 6 homozygotes. There are 572 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T301T) has been classified as Benign.

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., 134 hem., cov: 22)

Exomes 𝑓: 0.0012 ( 5 hom. 438 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 1.06

Publications

6 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=0.005182892).

BP6

Variant X-68206604-G-A is Benign according to our data. Variant chrX-68206604-G-A is described in ClinVar as Benign. ClinVar VariationId is 159480.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.004 (448/112000) while in subpopulation AFR AF = 0.0109 (337/30889). AF 95% confidence interval is 0.00995. There are 1 homozygotes in GnomAd4. There are 134 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 134 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3 link	c.902C>T	p.Thr301Met	missense_variant	Exon 10 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.902C>T	p.Thr301Met	missense_variant	Exon 10 of 25	1	NM_002547.3	ENSP00000347710.5		O60890-1

Frequencies

GnomAD3 genomes

AF:

0.00401

AC:

449

AN:

111946

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0110

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00407

Gnomad ASJ

AF:

0.00189

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000373

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0170

Gnomad NFE

AF:

0.000996

Gnomad OTH

AF:

0.00329

GnomAD2 exomes

AF:

0.00223

AC:

409

AN:

183356

AF XY:

0.00195

show subpopulations

Gnomad AFR exome

AF:

0.0116

Gnomad AMR exome

AF:

0.00459

Gnomad ASJ exome

AF:

0.00174

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000626

Gnomad NFE exome

AF:

0.00101

Gnomad OTH exome

AF:

0.00663

GnomAD4 exome

AF:

0.00118

AC:

1298

AN:

1096730

Hom.:

Cov.:

AF XY:

0.00121

AC XY:

438

AN XY:

362136

show subpopulations

African (AFR)

AF:

0.0129

AC:

341

AN:

26368

American (AMR)

AF:

0.00491

AC:

173

AN:

35206

Ashkenazi Jewish (ASJ)

AF:

0.00181

AC:

AN:

19371

East Asian (EAS)

AF:

0.0000662

AC:

AN:

30203

South Asian (SAS)

AF:

0.000111

AC:

AN:

54118

European-Finnish (FIN)

AF:

0.0000740

AC:

AN:

40515

Middle Eastern (MID)

AF:

0.00605

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.000718

AC:

604

AN:

840769

Other (OTH)

AF:

0.00237

AC:

109

AN:

46047

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

139

186

232

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

150

<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:

0.00400

AC:

448

AN:

112000

Hom.:

Cov.:

AF XY:

0.00392

AC XY:

134

AN XY:

34190

show subpopulations

African (AFR)

AF:

0.0109

AC:

337

AN:

30889

American (AMR)

AF:

0.00407

AC:

AN:

10566

Ashkenazi Jewish (ASJ)

AF:

0.00189

AC:

AN:

2650

East Asian (EAS)

AF:

0.00

AC:

AN:

3550

South Asian (SAS)

AF:

0.000375

AC:

AN:

2670

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6019

Middle Eastern (MID)

AF:

0.0186

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.000996

AC:

AN:

53221

Other (OTH)

AF:

0.00325

AC:

AN:

1538

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00187

Hom.:

Bravo

AF:

0.00495

TwinsUK

AF:

0.00135

AC:

ALSPAC

AF:

0.000346

AC:

ESP6500AA

AF:

0.0112

AC:

ESP6500EA

AF:

0.00119

AC:

ExAC

AF:

0.00254

AC:

308

EpiCase

AF:

0.00125

EpiControl

AF:

0.00166

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Sep 15, 2016

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 31, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not specified

Benign:2

Jul 30, 2015

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. -

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

X-linked intellectual disability-cerebellar hypoplasia syndrome

Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Sep 17, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Sep 06, 2016

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. -

OPHN1-related disorder

Benign:1

Aug 07, 2024

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.054

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.91

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.17

LIST_S2

Benign

0.67

MetaRNN

Benign

0.0052

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

1.1

PrimateAI

Benign

0.38

PROVEAN

Benign

0.52

REVEL

Benign

0.019

Sift

Benign

0.22

Sift4G

Benign

0.098

Polyphen

0.0080

Vest4

0.17

MVP

0.19

MPC

1.0

ClinPred

0.0029

GERP RS

0.34

Varity_R

0.028

gMVP

0.52

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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