10-86659948-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033282.4(OPN4):c.854G>A(p.Arg285Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000793 in 1,614,048 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: OPN4 NM_033282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.42

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.042334795).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPN4	NM_033282.4	c.854G>A	p.Arg285Gln	missense_variant	6/10	ENST00000241891.10
LOC105378409	XR_001747526.2	n.382-1654C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPN4	ENST00000241891.10	c.854G>A	p.Arg285Gln	missense_variant	6/10	1	NM_033282.4	P1
OPN4	ENST00000372071.7	c.887G>A	p.Arg296Gln	missense_variant	7/11	1
OPN4	ENST00000686083.1	n.1553G>A		non_coding_transcript_exon_variant	3/3
OPN4	ENST00000690949.1	n.888G>A		non_coding_transcript_exon_variant	7/11

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152226 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000637 AC: 16 AN: 251106 Hom.: 0 AF XY: 0.0000368 AC XY: 5 AN XY: 135816

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.0000925

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000800 AC: 117 AN: 1461822 Hom.: 0 Cov.: 32 AF XY: 0.0000784 AC XY: 57 AN XY: 727220

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.0000710

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152226 Hom.: 0 Cov.: 33 AF XY: 0.0000672 AC XY: 5 AN XY: 74364

Gnomad4 AFR AF: 0.0000965

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000906 AC: 11

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 01, 2021

The c.887G>A (p.R296Q) alteration is located in exon 7 (coding exon 7) of the OPN4 gene. This alteration results from a G to A substitution at nucleotide position 887, causing the arginine (R) at amino acid position 296 to be replaced by a glutamine (Q). 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	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.62	T;T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.92	N;N;N
REVEL	Benign	0.057
Sift	Benign	0.31	T;T;T
Sift4G	Benign	0.33	T;T;T
Polyphen		0.79	P;B;B
Vest4		0.16
MVP		0.29
MPC		0.057
ClinPred		0.026	T
GERP RS		2.2
Varity_R		0.023
gMVP		0.24

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: rs137979675; hg19: chr10-88419705;