rs374431961

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_002547.3(OPHN1):c.2168A>G(p.Asp723Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,207,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D723E) has been classified as Benign.

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., 5 hem., cov: 22)

Exomes 𝑓: 0.00015 ( 0 hom. 71 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 4.50

Publications

3 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.09635338).

BP6

Variant X-68053801-T-C is Benign according to our data. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439. Variant chrX-68053801-T-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 437439.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000127 (14/110540) while in subpopulation SAS AF = 0.000786 (2/2546). AF 95% confidence interval is 0.000139. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 22. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3 link	c.2168A>G	p.Asp723Gly	missense_variant	Exon 22 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.2168A>G	p.Asp723Gly	missense_variant	Exon 22 of 25	1	NM_002547.3	ENSP00000347710.5		O60890-1

Frequencies

GnomAD3 genomes

AF:

0.000127

AC:

AN:

110540

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000330

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000786

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000208

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000230

AC:

AN:

178432

AF XY:

0.000235

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000259

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000290

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000150

AC:

165

AN:

1096645

Hom.:

Cov.:

AF XY:

0.000196

AC XY:

AN XY:

362213

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26398

American (AMR)

AF:

0.000199

AC:

AN:

35089

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19244

East Asian (EAS)

AF:

0.00

AC:

AN:

30186

South Asian (SAS)

AF:

0.000598

AC:

AN:

53540

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40454

Middle Eastern (MID)

AF:

0.000729

AC:

AN:

4118

European-Non Finnish (NFE)

AF:

0.000134

AC:

113

AN:

841588

Other (OTH)

AF:

0.000152

AC:

AN:

46028

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome 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

GnomAD4 genome

AF:

0.000127

AC:

AN:

110540

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

AN XY:

32752

show subpopulations

African (AFR)

AF:

0.0000330

AC:

AN:

30302

American (AMR)

AF:

0.00

AC:

AN:

10342

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2636

East Asian (EAS)

AF:

0.00

AC:

AN:

3549

South Asian (SAS)

AF:

0.000786

AC:

AN:

2546

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5899

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000208

AC:

AN:

52859

Other (OTH)

AF:

0.00

AC:

AN:

1484

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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:

0.000285

Hom.:

Bravo

AF:

0.000136

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000149

AC:

ExAC

AF:

0.000272

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

OPHN1: BS2 -

Sep 11, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19377476) -

X-linked intellectual disability-cerebellar hypoplasia syndrome

Uncertain:1

Jan 01, 2019

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Jun 29, 2018

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

Nov 01, 2021

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

0.099

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.44

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.18

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.79

M_CAP

Benign

0.038

MetaRNN

Benign

0.096

MetaSVM

Benign

-0.95

MutationAssessor

Uncertain

2.0

PhyloP100

4.5

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-1.4

REVEL

Benign

0.10

Sift

Uncertain

0.025

Sift4G

Benign

0.083

Polyphen

0.44

Vest4

0.082

MVP

0.65

MPC

0.22

ClinPred

0.36

GERP RS

4.8

Varity_R

0.30

gMVP

0.32

Mutation Taster

=93/7

polymorphism

(source)

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

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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