Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_002547.3(OPHN1):c.746T>C(p.Leu249Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 22)

Consequence

OPHN1
NM_002547.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 8.25

Publications

0 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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.827

PP5

Variant X-68210239-A-G is Pathogenic according to our data. Variant chrX-68210239-A-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 374192.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	NM_002547.3	MANE Select	c.746T>C	p.Leu249Pro	missense	Exon 9 of 25	NP_002538.1
	OPHN1	NM_001437258.1		c.746T>C	p.Leu249Pro	missense	Exon 9 of 24	NP_001424187.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.746T>C	p.Leu249Pro	missense	Exon 9 of 25	ENSP00000347710.5
OPHN1	ENST00000681408.1		c.641T>C	p.Leu214Pro	missense	Exon 8 of 24	ENSP00000506619.1
OPHN1	ENST00000679748.1		c.746T>C	p.Leu249Pro	missense	Exon 9 of 24	ENSP00000505800.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions as Germline

Significance:Likely pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Nystagmus;C0036572:Seizure;C0079924:Oligohydramnios;C0344482:Hypoplasia of the corpus callosum;C1837658:Delayed gross motor development;C5231391:Congenital cerebellar hypoplasia (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Uncertain

-0.020

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.21

MetaRNN

Pathogenic

0.83

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.8

PhyloP100

8.3

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-6.2

REVEL

Uncertain

0.43

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.91

MutPred

0.32

Gain of glycosylation at L249 (P = 0.0162)

MVP

0.94

MPC

2.6

ClinPred

1.0

GERP RS

3.6

PromoterAI

0.013

Neutral

(source)

Varity_R

0.98

gMVP

1.0

Mutation Taster

=8/92

disease causing (ClinVar)

(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

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rs1057518963

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over