rs148208753

chrX-68052553-G-AchrX-68052553-G-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_002547.3(OPHN1):c.2362C>T(p.Arg788Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000124 in 1,204,966 control chromosomes in the GnomAD database, including 1 homozygotes. There are 48 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R788Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., 3 hem., cov: 23)
  • Exomes 𝑓: 0.00012 (1 hom. 45 hem.)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.92

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077751756).
• BP6: Variant X-68052553-G-A is Benign according to our data. Variant chrX-68052553-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 378314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-68052553-G-A is described in Lovd as [Likely_benign].
• BS2: High Hemizygotes in GnomAd at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.2362C>T	p.Arg788Trp	missense_variant	23/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.2362C>T	p.Arg788Trp	missense_variant	23/25	1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.000161 AC: 18 AN: 111815 Hom.: 0 Cov.: 23 AF XY: 0.0000882 AC XY: 3 AN XY: 34021

Gnomad AFR AF: 0.000163

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000945

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: 0.000207

Gnomad OTH AF: 0.000667

GnomAD3 exomes AF: 0.000240 AC: 41 AN: 170737 Hom.: 2 AF XY: 0.000246 AC XY: 14 AN XY: 56881

Gnomad AFR exome AF: 0.000243

Gnomad AMR exome AF: 0.000604

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000757

Gnomad SAS exome AF: 0.0000584

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000201

Gnomad OTH exome AF: 0.00117

GnomAD4 exome AF: 0.000121 AC: 132 AN: 1093151 Hom.: 1 Cov.: 30 AF XY: 0.000125 AC XY: 45 AN XY: 359309

Gnomad4 AFR exome AF: 0.000569

Gnomad4 AMR exome AF: 0.000519

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000566

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.000161 AC: 18 AN: 111815 Hom.: 0 Cov.: 23 AF XY: 0.0000882 AC XY: 3 AN XY: 34021

Gnomad4 AFR AF: 0.000163

Gnomad4 AMR AF: 0.0000945

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000207

Gnomad4 OTH AF: 0.000667

Alfa AF: 0.000141 Hom.: 2

Bravo AF: 0.000181

ESP6500AA AF: 0.000261 AC: 1

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000289 AC: 35

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2020	This variant is associated with the following publications: (PMID: 23552953) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	OPHN1: PM5, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 16, 2024	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Aug 23, 2018

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2017

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. -

X-linked intellectual disability-cerebellar hypoplasia syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Sep 29, 2021

- -

OPHN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2021

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	0.22
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.50
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.082	D
MetaRNN	Benign	0.078	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.19
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.17
MVP		0.37
MPC		0.41
ClinPred		0.084	T
GERP RS		2.0
Varity_R		0.21
gMVP		0.42

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

LitVar

Other links and lift over

dbSNP: rs148208753; hg19: chrX-67272395;