X-68432965-C-T

Variant names:

• chrX-68432965-C-T
• rs1555988278
• NM_002547.3:c.56G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_002547.3(OPHN1):​c.56G>A​(p.Arg19His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R19P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 24)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.36
• Publications: 0 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: Orphanet, ClinGen, G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 25	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6	c.56G>A	p.Arg19His	missense_variant	Exon 2 of 25	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 24

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Apr 13, 2017

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.31	T
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.090	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.70	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.4
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.45
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.88
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		-0.044	Neutral
Varity_R		0.76
gMVP		0.97
Mutation Taster		=28/72	disease causing

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

Other links and lift over

dbSNP: rs1555988278; hg19: chrX-67652807; COSMIC: COSV62784569;