chrX-68053654-G-T

Variant names:

• chrX-68053654-G-T
• rs1451445409
• NM_002547.3:c.2315C>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.2315C>A​(p.Thr772Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,720 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: OPHN1 NM_002547.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.90

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=0.12032437).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
OPHN1	NM_002547.3	c.2315C>A	p.Thr772Lys	missense_variant	Exon 22 of 25	ENST00000355520.6	NP_002538.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPHN1	ENST00000355520.6	c.2315C>A	p.Thr772Lys	missense_variant	Exon 22 of 25	1	NM_002547.3	ENSP00000347710.5

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000549 AC: 1 AN: 182031 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 66595

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: 0.0000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097720 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363098

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	21
DANN	Benign	0.95
DEOGEN2	Benign	0.074	T
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.34	N
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.47	N
REVEL	Benign	0.039
Sift	Uncertain	0.011	D
Sift4G	Benign	0.23	T
Polyphen		0.0020	B
Vest4		0.24
MutPred		0.40		Gain of ubiquitination at T772 (P = 0.0039);
MVP		0.20
MPC		0.14
ClinPred		0.36	T
GERP RS		3.1
Varity_R		0.18
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1451445409; hg19: chrX-67273496;