X-68048534-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002547.3(OPHN1):c.2376-77G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.112 in 918,108 control chromosomes in the GnomAD database, including 5,113 homozygotes. There are 31,708 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.14 (1062 hom., 4526 hem., cov: 23)
  • Exomes 𝑓: 0.11 (4051 hom. 27182 hem.)
• Consequence: OPHN1 NM_002547.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0960

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 (BayesDel_noAF=-0.86).
• BP6: Variant X-68048534-C-A is Benign according to our data. Variant chrX-68048534-C-A is described in ClinVar as [Benign]. Clinvar id is 674158.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.2376-77G>T		intron_variant		ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.2376-77G>T		intron_variant		1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.139 AC: 15469 AN: 111510 Hom.: 1054 Cov.: 23 AF XY: 0.134 AC XY: 4509 AN XY: 33712

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.0203

Gnomad AMR AF: 0.185

Gnomad ASJ AF: 0.0753

Gnomad EAS AF: 0.281

Gnomad SAS AF: 0.232

Gnomad FIN AF: 0.0338

Gnomad MID AF: 0.113

Gnomad NFE AF: 0.0792

Gnomad OTH AF: 0.160

GnomAD4 exome AF: 0.108 AC: 87091 AN: 806544 Hom.: 4051 AF XY: 0.129 AC XY: 27182 AN XY: 210642

Gnomad4 AFR exome AF: 0.246

Gnomad4 AMR exome AF: 0.223

Gnomad4 ASJ exome AF: 0.0807

Gnomad4 EAS exome AF: 0.234

Gnomad4 SAS exome AF: 0.236

Gnomad4 FIN exome AF: 0.0370

Gnomad4 NFE exome AF: 0.0845

Gnomad4 OTH exome AF: 0.127

GnomAD4 genome AF: 0.139 AC: 15495 AN: 111564 Hom.: 1062 Cov.: 23 AF XY: 0.134 AC XY: 4526 AN XY: 33776

Gnomad4 AFR AF: 0.230

Gnomad4 AMR AF: 0.185

Gnomad4 ASJ AF: 0.0753

Gnomad4 EAS AF: 0.281

Gnomad4 SAS AF: 0.232

Gnomad4 FIN AF: 0.0338

Gnomad4 NFE AF: 0.0792

Gnomad4 OTH AF: 0.171

Alfa AF: 0.104 Hom.: 2166

Bravo AF: 0.160

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	2.2
Dann	Benign	0.45

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

LitVar

Other links and lift over

dbSNP: rs2148827; hg19: chrX-67268376; COSMIC: COSV62781940;