chrX-68053659-T-A

Position:

• chrX-68053659-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002547.3(OPHN1):​c.2310A>T​(p.Glu770Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.353

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09965971).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPHN1	NM_002547.3	c.2310A>T	p.Glu770Asp	missense_variant	22/25	ENST00000355520.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPHN1	ENST00000355520.6	c.2310A>T	p.Glu770Asp	missense_variant	22/25	1	NM_002547.3	P1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2023

The c.2310A>T (p.E770D) alteration is located in exon 22 (coding exon 21) of the OPHN1 gene. This alteration results from a A to T substitution at nucleotide position 2310, causing the glutamic acid (E) at amino acid position 770 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.054
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.97
CADD	Benign	11
DANN	Benign	0.97
DEOGEN2	Benign	0.095	T
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.63	T
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.13
Sift	Benign	0.12	T
Sift4G	Benign	0.43	T
Polyphen		0.0010	B
Vest4		0.16
MutPred		0.11		Loss of solvent accessibility (P = 0.1177);
MVP		0.50
MPC		0.11
ClinPred		0.59	D
GERP RS		-4.3
Varity_R		0.096
gMVP		0.059

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-67273501;