X-68053635-C-A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3 BP6_Very_Strong BS2

The NM_002547.3(OPHN1):c.2324+10G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000476 in 1,208,632 control chromosomes in the GnomAD database, including 1 homozygotes. There are 159 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., 77 hem., cov: 22)
  • Exomes 𝑓: 0.00028 (0 hom. 82 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.515

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 -11 ACMG points.

• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant X-68053635-C-A is Benign according to our data. Variant chrX-68053635-C-A is described in ClinVar as [Benign]. Clinvar id is 195675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd at 77 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.2324+10G>T		intron_variant		ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.2324+10G>T		intron_variant		1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.00238 AC: 266 AN: 111752 Hom.: 1 Cov.: 22 AF XY: 0.00227 AC XY: 77 AN XY: 33942

Gnomad AFR AF: 0.00784

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00143

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0168

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.000731 AC: 132 AN: 180657 Hom.: 0 AF XY: 0.000566 AC XY: 37 AN XY: 65331

Gnomad AFR exome AF: 0.00885

Gnomad AMR exome AF: 0.000293

Gnomad ASJ exome AF: 0.000135

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000621

Gnomad OTH exome AF: 0.000670

GnomAD4 exome AF: 0.000281 AC: 308 AN: 1096828 Hom.: 0 Cov.: 30 AF XY: 0.000226 AC XY: 82 AN XY: 362266

Gnomad4 AFR exome AF: 0.00875

Gnomad4 AMR exome AF: 0.000455

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000178

Gnomad4 OTH exome AF: 0.000955

GnomAD4 genome AF: 0.00239 AC: 267 AN: 111804 Hom.: 1 Cov.: 22 AF XY: 0.00226 AC XY: 77 AN XY: 34004

Gnomad4 AFR AF: 0.00786

Gnomad4 AMR AF: 0.00143

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00199

Alfa AF: 0.000879 Hom.: 8

Bravo AF: 0.00291

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 12, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 25, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Apr 21, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	18
Dann	Benign	0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.57		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.57		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs144475530; hg19: chrX-67273477;