rs374431961

chrX-68053801-T-C

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_002547.3(OPHN1):c.2168A>G(p.Asp723Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,207,185 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 76 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D723E) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 5 hem., cov: 22)
  • Exomes 𝑓: 0.00015 (0 hom. 71 hem.)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 4.50

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.09635338).
• BP6: Variant X-68053801-T-C is Benign according to our data. Variant chrX-68053801-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 437439.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAd at 5 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.2168A>G	p.Asp723Gly	missense_variant	22/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.2168A>G	p.Asp723Gly	missense_variant	22/25	1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 14 AN: 110540 Hom.: 0 Cov.: 22 AF XY: 0.000153 AC XY: 5 AN XY: 32752

Gnomad AFR AF: 0.0000330

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000786

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000208

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000230 AC: 41 AN: 178432 Hom.: 0 AF XY: 0.000235 AC XY: 15 AN XY: 63742

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000259

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000608

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000290

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000150 AC: 165 AN: 1096645 Hom.: 0 Cov.: 31 AF XY: 0.000196 AC XY: 71 AN XY: 362213

Gnomad4 AFR exome AF: 0.000114

Gnomad4 AMR exome AF: 0.000199

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000598

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000134

Gnomad4 OTH exome AF: 0.000152

GnomAD4 genome AF: 0.000127 AC: 14 AN: 110540 Hom.: 0 Cov.: 22 AF XY: 0.000153 AC XY: 5 AN XY: 32752

Gnomad4 AFR AF: 0.0000330

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000786

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000208

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000285 Hom.: 1

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.000272 AC: 33

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Oct 24, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 11, 2020	This variant is associated with the following publications: (PMID: 19377476) -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Jan 01, 2019

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2018

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. -

OPHN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 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	0.099
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.18	T
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.096	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.10
Sift	Uncertain	0.025	D
Sift4G	Benign	0.083	T
Polyphen		0.44	B
Vest4		0.082
MVP		0.65
MPC		0.22
ClinPred		0.36	T
GERP RS		4.8
Varity_R		0.30
gMVP		0.32

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: rs374431961; hg19: chrX-67273643; COSMIC: COSV62783290;