rs148262378

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.133G>A(p.Ala45Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00155 in 1,210,661 control chromosomes in the GnomAD database, including 4 homozygotes. There are 587 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0013 ( 1 hom., 38 hem., cov: 24)

Exomes 𝑓: 0.0016 ( 3 hom. 549 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -1.11

Publications

8 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: ClinGen, G2P, Ambry Genetics, Orphanet, 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=0.0061807036).

BP6

Variant X-68432888-C-T is Benign according to our data. Variant chrX-68432888-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94073.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00131 (148/112716) while in subpopulation NFE AF = 0.00206 (110/53331). AF 95% confidence interval is 0.00175. There are 1 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 24. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 38 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002547.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	NM_002547.3	MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 2 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.133G>A	p.Ala45Thr	missense	Exon 2 of 24	NP_001424187.1	A0A7P0Z4E9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.133G>A	p.Ala45Thr	missense	Exon 2 of 25	ENSP00000347710.5	O60890-1
OPHN1	ENST00000905069.1		c.133G>A	p.Ala45Thr	missense	Exon 2 of 25	ENSP00000575128.1
OPHN1	ENST00000681408.1		c.133G>A	p.Ala45Thr	missense	Exon 2 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

148

AN:

112663

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000257

Gnomad AMI

AF:

0.0322

Gnomad AMR

AF:

0.000562

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:

0.00206

Gnomad OTH

AF:

0.00132

GnomAD2 exomes

AF:

0.000906

AC:

166

AN:

183238

AF XY:

0.000931

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000583

Gnomad ASJ exome

AF:

0.000267

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00171

Gnomad OTH exome

AF:

0.00110

GnomAD4 exome

AF:

0.00158

AC:

1734

AN:

1097945

Hom.:

Cov.:

AF XY:

0.00151

AC XY:

549

AN XY:

363305

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26396

American (AMR)

AF:

0.000540

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.000206

AC:

AN:

19385

East Asian (EAS)

AF:

0.0000331

AC:

AN:

30205

South Asian (SAS)

AF:

0.0000739

AC:

AN:

54142

European-Finnish (FIN)

AF:

0.000247

AC:

AN:

40474

Middle Eastern (MID)

AF:

0.000484

AC:

AN:

4135

European-Non Finnish (NFE)

AF:

0.00193

AC:

1621

AN:

841916

Other (OTH)

AF:

0.00152

AC:

AN:

46087

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

132

197

263

329

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00131

AC:

148

AN:

112716

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

34852

show subpopulations

African (AFR)

AF:

0.000257

AC:

AN:

31147

American (AMR)

AF:

0.000562

AC:

AN:

10682

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3557

South Asian (SAS)

AF:

0.00

AC:

AN:

2732

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6178

Middle Eastern (MID)

AF:

0.00

AC:

AN:

218

European-Non Finnish (NFE)

AF:

0.00206

AC:

110

AN:

53331

Other (OTH)

AF:

0.00131

AC:

AN:

1532

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

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:

0.00159

Hom.:

Bravo

AF:

0.00143

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00208

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00178

AC:

ExAC

AF:

0.000881

AC:

107

EpiCase

AF:

0.00180

EpiControl

AF:

0.00202

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (3)

Inborn genetic diseases (1)

X-linked intellectual disability-cerebellar hypoplasia syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.84

BayesDel_noAF

Benign

-0.98

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.042

FATHMM_MKL

Benign

0.039

LIST_S2

Uncertain

0.92

M_CAP

Benign

0.0096

MetaRNN

Benign

0.0062

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.4

PhyloP100

-1.1

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.22

REVEL

Benign

0.028

Sift

Benign

0.57

Sift4G

Benign

0.63

Polyphen

0.46

Vest4

0.049

MVP

0.58

MPC

0.96

ClinPred

0.0056

GERP RS

-0.81

PromoterAI

-0.028

Neutral

(source)

Varity_R

0.051

gMVP

0.48

Mutation Taster

=97/3

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over