10-86662359-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.1181C>T(p.Thr394Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.661 in 1,587,300 control chromosomes in the GnomAD database, including 348,612 homozygotes. 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.70 (37389 hom., cov: 34)
  • Exomes 𝑓: 0.66 (311223 hom.)
• Consequence: OPN4 NM_033282.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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]

LOC105378409 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.919383E-7).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.773 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPN4	NM_033282.4	c.1181C>T	p.Thr394Ile	missense_variant	8/10	ENST00000241891.10
LOC105378409	XR_001747526.2	n.381+559G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPN4	ENST00000241891.10	c.1181C>T	p.Thr394Ile	missense_variant	8/10	1	NM_033282.4	P1
OPN4	ENST00000372071.7	c.1214C>T	p.Thr405Ile	missense_variant	9/11	1
OPN4	ENST00000690949.1	n.1215C>T		non_coding_transcript_exon_variant	9/11

Frequencies

GnomAD3 genomes AF: 0.698 AC: 106054 AN: 151996 Hom.: 37329 Cov.: 34

Gnomad AFR AF: 0.771

Gnomad AMI AF: 0.785

Gnomad AMR AF: 0.711

Gnomad ASJ AF: 0.702

Gnomad EAS AF: 0.793

Gnomad SAS AF: 0.746

Gnomad FIN AF: 0.683

Gnomad MID AF: 0.665

Gnomad NFE AF: 0.641

Gnomad OTH AF: 0.677

GnomAD3 exomes AF: 0.696 AC: 144303 AN: 207440 Hom.: 50482 AF XY: 0.692 AC XY: 77248 AN XY: 111698

Gnomad AFR exome AF: 0.781

Gnomad AMR exome AF: 0.746

Gnomad ASJ exome AF: 0.689

Gnomad EAS exome AF: 0.799

Gnomad SAS exome AF: 0.738

Gnomad FIN exome AF: 0.675

Gnomad NFE exome AF: 0.643

Gnomad OTH exome AF: 0.667

GnomAD4 exome AF: 0.657 AC: 942279 AN: 1435186 Hom.: 311223 Cov.: 56 AF XY: 0.657 AC XY: 467777 AN XY: 711478

Gnomad4 AFR exome AF: 0.777

Gnomad4 AMR exome AF: 0.744

Gnomad4 ASJ exome AF: 0.695

Gnomad4 EAS exome AF: 0.798

Gnomad4 SAS exome AF: 0.737

Gnomad4 FIN exome AF: 0.677

Gnomad4 NFE exome AF: 0.636

Gnomad4 OTH exome AF: 0.667

GnomAD4 genome AF: 0.698 AC: 106171 AN: 152114 Hom.: 37389 Cov.: 34 AF XY: 0.704 AC XY: 52336 AN XY: 74334

Gnomad4 AFR AF: 0.771

Gnomad4 AMR AF: 0.712

Gnomad4 ASJ AF: 0.702

Gnomad4 EAS AF: 0.793

Gnomad4 SAS AF: 0.746

Gnomad4 FIN AF: 0.683

Gnomad4 NFE AF: 0.641

Gnomad4 OTH AF: 0.679

Alfa AF: 0.655 Hom.: 49950

Bravo AF: 0.702

TwinsUK AF: 0.622 AC: 2307

ALSPAC AF: 0.638 AC: 2459

ESP6500AA AF: 0.768 AC: 3374

ESP6500EA AF: 0.646 AC: 5544

ExAC AF: 0.669 AC: 79490

Asia WGS AF: 0.773 AC: 2687 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	14
Dann	Benign	0.80
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.79
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.053	T;T;T
MetaRNN	Benign	7.9e-7	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.66	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.032
MPC		0.055
ClinPred		0.0012	T
GERP RS		1.1
Varity_R		0.042
gMVP		0.51

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: rs1079610; hg19: chr10-88422116; COSMIC: COSV54117289;