dbSNP rs192628082: OPHN1:p.Arg788Gln (chrX-68052552-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_002547.3(OPHN1):c.2363G>A(p.Arg788Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000266 in 1,205,036 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 3 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R788W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000071 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000022 ( 0 hom. 2 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 2.74

Publications

2 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: Likely_benign. The variant received -1 ACMG points.

BS2

High Hemizygotes in GnomAdExome4 at 2 XL geneVariant has number of hemizygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2363G>A	p.Arg788Gln	missense	Exon 23 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.2039G>A	p.Arg680Gln	missense	Exon 22 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.2363G>A	p.Arg788Gln	missense	Exon 23 of 25	ENSP00000347710.5	O60890-1
OPHN1	ENST00000905069.1		c.2363G>A	p.Arg788Gln	missense	Exon 23 of 25	ENSP00000575128.1
OPHN1	ENST00000681408.1		c.2258G>A	p.Arg753Gln	missense	Exon 22 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes

AF:

0.0000715

AC:

AN:

111859

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000326

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000944

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000281

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000752

Gnomad OTH

AF:

0.000665

GnomAD2 exomes

AF:

0.0000411

AC:

AN:

170427

AF XY:

0.0000177

show subpopulations

Gnomad AFR exome

AF:

0.0000811

Gnomad AMR exome

AF:

0.0000378

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000756

Gnomad FIN exome

AF:

0.0000656

Gnomad NFE exome

AF:

0.0000268

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000220

AC:

AN:

1093126

Hom.:

Cov.:

AF XY:

0.00000557

AC XY:

AN XY:

359282

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26350

American (AMR)

AF:

0.0000288

AC:

AN:

34700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19273

East Asian (EAS)

AF:

0.0000996

AC:

AN:

30113

South Asian (SAS)

AF:

0.0000378

AC:

AN:

52928

European-Finnish (FIN)

AF:

0.0000248

AC:

AN:

40272

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4125

European-Non Finnish (NFE)

AF:

0.0000203

AC:

AN:

839420

Other (OTH)

AF:

0.00

AC:

AN:

45945

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

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:

0.0000715

AC:

AN:

111910

Hom.:

Cov.:

AF XY:

0.0000293

AC XY:

AN XY:

34110

show subpopulations

African (AFR)

AF:

0.0000325

AC:

AN:

30777

American (AMR)

AF:

0.0000943

AC:

AN:

10607

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2648

East Asian (EAS)

AF:

0.000282

AC:

AN:

3549

South Asian (SAS)

AF:

0.00

AC:

AN:

2667

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6069

Middle Eastern (MID)

AF:

0.00

AC:

AN:

215

European-Non Finnish (NFE)

AF:

0.0000752

AC:

AN:

53170

Other (OTH)

AF:

0.000657

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.532

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.0000379

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.0000495

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

not provided (1)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.58

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.16

FATHMM_MKL

Uncertain

0.84

LIST_S2

Uncertain

0.86

M_CAP

Pathogenic

0.30

MetaRNN

Uncertain

0.42

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PhyloP100

2.7

PrimateAI

Uncertain

0.65

PROVEAN

Benign

-0.96

REVEL

Benign

0.10

Sift

Uncertain

0.017

Sift4G

Benign

0.11

Polyphen

0.99

Vest4

0.61

MVP

0.45

MPC

0.31

ClinPred

0.99

GERP RS

3.9

Varity_R

0.32

gMVP

0.34

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.14

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