rs763066236

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6BS1BS2_Supporting

The NM_002547.3(OPHN1):c.215T>C(p.Ile72Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000117 in 1,194,416 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.000012 ( 0 hom. 2 hem. )

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 6.23

Publications

1 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 -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.26991403).

BP6

Variant X-68299036-A-G is Benign according to our data. Variant chrX-68299036-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 437438.

BS1

Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000012 (13/1082048) while in subpopulation AMR AF = 0.000115 (4/34855). AF 95% confidence interval is 0.0000387. There are 0 homozygotes in GnomAdExome4. There are 2 alleles in the male GnomAdExome4 subpopulation. Median coverage is 26. This position passed quality control check.

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3 link	c.215T>C	p.Ile72Thr	missense_variant	Exon 3 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.215T>C	p.Ile72Thr	missense_variant	Exon 3 of 25	1	NM_002547.3	ENSP00000347710.5		O60890-1

Frequencies

GnomAD3 genomes

AF:

0.00000890

AC:

AN:

112368

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000660

GnomAD2 exomes

AF:

0.0000655

AC:

AN:

183252

AF XY:

0.0000295

show subpopulations

Gnomad AFR exome

AF:

0.0000760

Gnomad AMR exome

AF:

0.000182

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000144

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000367

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000120

AC:

AN:

1082048

Hom.:

Cov.:

AF XY:

0.00000572

AC XY:

AN XY:

349812

show subpopulations

African (AFR)

AF:

0.0000384

AC:

AN:

26030

American (AMR)

AF:

0.000115

AC:

AN:

34855

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18982

East Asian (EAS)

AF:

0.00

AC:

AN:

29490

South Asian (SAS)

AF:

0.0000186

AC:

AN:

53690

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39585

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4068

European-Non Finnish (NFE)

AF:

0.00000843

AC:

AN:

830117

Other (OTH)

AF:

0.00

AC:

AN:

45231

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.00000890

AC:

AN:

112368

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34516

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30973

American (AMR)

AF:

0.00

AC:

AN:

10538

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00

AC:

AN:

3574

South Asian (SAS)

AF:

0.00

AC:

AN:

2714

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6139

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53341

Other (OTH)

AF:

0.000660

AC:

AN:

1516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.625

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:

0.00

Hom.:

Bravo

AF:

0.0000718

ExAC

AF:

0.0000824

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

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

- -

not provided

Benign:1

Dec 31, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.36

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.26

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.92

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.80

MutationAssessor

Uncertain

2.6

PhyloP100

6.2

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-4.5

REVEL

Benign

0.28

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0030

Polyphen

0.64

Vest4

0.18

MutPred

0.61

Loss of stability (P = 0.0131);

MVP

0.72

MPC

2.0

ClinPred

0.68

GERP RS

3.7

Varity_R

0.79

gMVP

0.90

Mutation Taster

=89/11

polymorphism

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over