rs797045849

Positions:

• chrX-68194477-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_002547.3(OPHN1):​c.1126A>G​(p.Lys376Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000155 in 1,094,477 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93

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]

OPHN1 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.36839214).
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.1126A>G	p.Lys376Glu	missense_variant	13/25	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6	c.1126A>G	p.Lys376Glu	missense_variant	13/25	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.0000164 AC: 3 AN: 183047 Hom.: 0 AF XY: 0.0000296 AC XY: 2 AN XY: 67597

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.000222

GnomAD4 exome AF: 0.0000155 AC: 17 AN: 1094477 Hom.: 0 Cov.: 28 AF XY: 0.0000167 AC XY: 6 AN XY: 360055

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.0000191

Gnomad4 OTH exome AF: 0.0000218

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 29, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.7	M
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.14
Sift	Benign	0.091	T
Sift4G	Benign	0.19	T
Polyphen		0.82	P
Vest4		0.47
MutPred		0.36		Loss of ubiquitination at K376 (P = 0.0098);
MVP		0.90
MPC		2.0
ClinPred		0.65	D
GERP RS		5.0
Varity_R		0.54
gMVP		0.87

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs797045849; hg19: chrX-67414319; COSMIC: COSV62781487;