10-86654812-C-T

Position:

• chr10-86654812-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_033282.4(OPN4):​c.29C>T​(p.Pro10Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.123 in 1,610,452 control chromosomes in the GnomAD database, including 13,482 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. P10P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.10 (995 hom., cov: 33)
  • Exomes 𝑓: 0.13 (12487 hom.)
• Consequence: OPN4 NM_033282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.767

Genes affected

OPN4 (HGNC:14449): (opsin 4) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. This gene encodes a photoreceptive opsin protein that is expressed within the ganglion and amacrine cell layers of the retina. In mouse, retinal ganglion cell axons expressing this gene projected to the suprachiasmatic nucleus and other brain nuclei involved in circadian photoentrainment. In mouse, this protein is coupled to a transient receptor potential (TRP) ion channel through a G protein signaling pathway and produces a physiologic light response via membrane depolarization and increased intracellular calcium. The protein functions as a sensory photopigment and may also have photoisomerase activity. Experiments with knockout mice indicate that this gene attenuates, but does not abolish, photoentrainment. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2008]

ENSG00000289258 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001470089).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
OPN4	NM_033282.4	c.29C>T	p.Pro10Leu	missense_variant	1/10	ENST00000241891.10	NP_150598.1
OPN4	NM_001030015.3	c.29C>T	p.Pro10Leu	missense_variant	1/11		NP_001025186.1
OPN4	XM_017016955.2	c.29C>T	p.Pro10Leu	missense_variant	1/10		XP_016872444.1
OPN4	XM_017016956.2	c.29C>T	p.Pro10Leu	missense_variant	1/9		XP_016872445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
OPN4	ENST00000241891.10	c.29C>T	p.Pro10Leu	missense_variant	1/10	1	NM_033282.4	ENSP00000241891.5
ENSG00000289258	ENST00000443292.2	c.29C>T	p.Pro10Leu	missense_variant	1/18	1		ENSP00000393132.2

Frequencies

GnomAD3 genomes AF: 0.103 AC: 15605 AN: 152120 Hom.: 996 Cov.: 33

Gnomad AFR AF: 0.0395

Gnomad AMI AF: 0.303

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.143

Gnomad EAS AF: 0.0444

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.111

GnomAD3 exomes AF: 0.105 AC: 26254 AN: 250784 Hom.: 1636 AF XY: 0.108 AC XY: 14655 AN XY: 135650

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.0738

Gnomad ASJ exome AF: 0.137

Gnomad EAS exome AF: 0.0391

Gnomad SAS exome AF: 0.0735

Gnomad FIN exome AF: 0.113

Gnomad NFE exome AF: 0.137

Gnomad OTH exome AF: 0.121

GnomAD4 exome AF: 0.126 AC: 183175 AN: 1458214 Hom.: 12487 Cov.: 32 AF XY: 0.125 AC XY: 90470 AN XY: 725218

Gnomad4 AFR exome AF: 0.0383

Gnomad4 AMR exome AF: 0.0792

Gnomad4 ASJ exome AF: 0.142

Gnomad4 EAS exome AF: 0.0512

Gnomad4 SAS exome AF: 0.0743

Gnomad4 FIN exome AF: 0.114

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.123

GnomAD4 genome AF: 0.103 AC: 15612 AN: 152238 Hom.: 995 Cov.: 33 AF XY: 0.102 AC XY: 7629 AN XY: 74432

Gnomad4 AFR AF: 0.0398

Gnomad4 AMR AF: 0.116

Gnomad4 ASJ AF: 0.143

Gnomad4 EAS AF: 0.0445

Gnomad4 SAS AF: 0.0771

Gnomad4 FIN AF: 0.115

Gnomad4 NFE AF: 0.137

Gnomad4 OTH AF: 0.110

Alfa AF: 0.127 Hom.: 2038

Bravo AF: 0.100

TwinsUK AF: 0.144 AC: 535

ALSPAC AF: 0.133 AC: 511

ESP6500AA AF: 0.0399 AC: 176

ESP6500EA AF: 0.135 AC: 1161

ExAC AF: 0.105 AC: 12797

Asia WGS AF: 0.0630 AC: 217 AN: 3478

EpiCase AF: 0.141

EpiControl AF: 0.149

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	0.42
DANN	Benign	0.27
DEOGEN2	Benign	0.085	.;T;.
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.58	T;T;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.67	N;N;N
REVEL	Benign	0.085
Sift	Benign	0.72	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;B;B
Vest4		0.064
MPC		0.052
ClinPred		0.00052	T
GERP RS		-2.1
Varity_R		0.017
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs2675703; hg19: chr10-88414569; COSMIC: COSV54115835;