rs143598006

chrX-68299002-G-AchrX-68299002-G-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_002547.3(OPHN1):c.249C>T(p.Ile83=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,151,141 control chromosomes in the GnomAD database, including 1 homozygotes. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. I83I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 0 hem., cov: 23)
  • Exomes 𝑓: 0.000031 (1 hom. 11 hem.)
• Consequence: OPHN1 NM_002547.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0003319
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.179

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant X-68299002-G-A is Benign according to our data. Variant chrX-68299002-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 436108.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.179 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.249C>T	p.Ile83=	splice_region_variant, synonymous_variant	3/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.249C>T	p.Ile83=	splice_region_variant, synonymous_variant	3/25	1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000357 AC: 4 AN: 112091 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34243

Gnomad AFR AF: 0.0000324

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000328 AC: 6 AN: 183172 Hom.: 0 AF XY: 0.0000295 AC XY: 2 AN XY: 67740

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000144

Gnomad SAS exome AF: 0.0000524

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000308 AC: 32 AN: 1038994 Hom.: 1 Cov.: 20 AF XY: 0.0000347 AC XY: 11 AN XY: 317218

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000289

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000693

Gnomad4 SAS exome AF: 0.0000759

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000114

Gnomad4 OTH exome AF: 0.0000688

GnomAD4 genome AF: 0.0000268 AC: 3 AN: 112147 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 34309

Gnomad4 AFR AF: 0.0000323

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 18, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
Cadd	Benign	1.8
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00033
dbscSNV1_RF	Benign	0.094
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: rs143598006; hg19: chrX-67518844; COSMIC: COSV62781104;