rs797045849

Variant names:

• chrX-68194477-T-C
• rs797045849
• NM_002547.3:c.1126A>G

Variant summary

Our verdict is Likely benign. The variant received -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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 4.93
• Publications: 1 publications found

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 Gene-Disease associations (from GenCC):

• X-linked intellectual disability-cerebellar hypoplasia syndrome

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002547.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	NM_002547.3	MANE Select	c.1126A>G	p.Lys376Glu	missense	Exon 13 of 25	NP_002538.1	O60890-1
	OPHN1	NM_001437258.1		c.1126A>G	p.Lys376Glu	missense	Exon 13 of 24	NP_001424187.1	A0A7P0Z4E9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	OPHN1	ENST00000355520.6	TSL:1 MANE Select	c.1126A>G	p.Lys376Glu	missense	Exon 13 of 25	ENSP00000347710.5	O60890-1
	OPHN1	ENST00000905069.1		c.1126A>G	p.Lys376Glu	missense	Exon 13 of 25	ENSP00000575128.1
	OPHN1	ENST00000681408.1		c.1021A>G	p.Lys341Glu	missense	Exon 12 of 24	ENSP00000506619.1	A0A7P0TBH4

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000164 AC: 3 AN: 183047 AF XY: 0.0000296

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 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

African (AFR) AF: 0.00 AC: 0 AN: 26322

American (AMR) AF: 0.00 AC: 0 AN: 35193

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19349

East Asian (EAS) AF: 0.00 AC: 0 AN: 30168

South Asian (SAS) AF: 0.00 AC: 0 AN: 54063

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40403

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4096

European-Non Finnish (NFE) AF: 0.0000191 AC: 16 AN: 838917

Other (OTH) AF: 0.0000218 AC: 1 AN: 45966

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		4.9
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
Mutation Taster		=94/6	polymorphism

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

Other links and lift over

dbSNP: rs797045849; hg19: chrX-67414319; COSMIC: COSV62781487;