rs368803937

chrX-68073156-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_002547.3(OPHN1):c.1830C>T(p.Ser610=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000896 in 1,205,325 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 36 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).

• Frequency:
  • Genomes: 𝑓 0.000071 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000091 (0 hom. 35 hem.)
• Consequence: OPHN1 NM_002547.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.519

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant X-68073156-G-A is Benign according to our data. Variant chrX-68073156-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=1}.
• BP7: Synonymous conserved (PhyloP=0.519 with no splicing effect.
• BS2: High Hemizygotes in GnomAdExome at 7 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.1830C>T	p.Ser610=	synonymous_variant	20/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.1830C>T	p.Ser610=	synonymous_variant	20/25	1	NM_002547.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000713 AC: 8 AN: 112267 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34439

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00151

Gnomad EAS AF: 0.000281

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000375

Gnomad OTH AF: 0.000665

GnomAD3 exomes AF: 0.000195 AC: 33 AN: 169245 Hom.: 0 AF XY: 0.000126 AC XY: 7 AN XY: 55647

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000759

Gnomad ASJ exome AF: 0.00275

Gnomad EAS exome AF: 0.000382

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000541

Gnomad OTH exome AF: 0.000473

GnomAD4 exome AF: 0.0000915 AC: 100 AN: 1093058 Hom.: 0 Cov.: 30 AF XY: 0.0000974 AC XY: 35 AN XY: 359184

Gnomad4 AFR exome AF: 0.0000760

Gnomad4 AMR exome AF: 0.0000576

Gnomad4 ASJ exome AF: 0.00207

Gnomad4 EAS exome AF: 0.000133

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000596

Gnomad4 OTH exome AF: 0.0000436

GnomAD4 genome AF: 0.0000713 AC: 8 AN: 112267 Hom.: 0 Cov.: 23 AF XY: 0.0000290 AC XY: 1 AN XY: 34439

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00151

Gnomad4 EAS AF: 0.000281

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000375

Gnomad4 OTH AF: 0.000665

Alfa AF: 0.000304 Hom.: 1

Bravo AF: 0.0000945

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	May 24, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 08, 2023	- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Dec 16, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
Cadd	Benign	6.8
Dann	Benign	0.88

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: rs368803937; hg19: chrX-67292998;