10-86658613-G-A

Variant summary

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

The NM_033282.4(OPN4):c.554G>A(p.Arg185Lys) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: OPN4 NM_033282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.39

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 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=0.07960287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPN4	NM_033282.4	c.554G>A	p.Arg185Lys	missense_variant	4/10	ENST00000241891.10
LOC105378409	XR_001747526.2	n.382-319C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPN4	ENST00000241891.10	c.554G>A	p.Arg185Lys	missense_variant	4/10	1	NM_033282.4	P1
OPN4	ENST00000372071.7	c.587G>A	p.Arg196Lys	missense_variant	5/11	1
OPN4	ENST00000686083.1	n.1253G>A		non_coding_transcript_exon_variant	1/3
OPN4	ENST00000690949.1	n.588G>A		non_coding_transcript_exon_variant	5/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

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

Jan 09, 2024

The c.587G>A (p.R196K) alteration is located in exon 5 (coding exon 5) of the OPN4 gene. This alteration results from a G to A substitution at nucleotide position 587, causing the arginine (R) at amino acid position 196 to be replaced by a lysine (K). 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	0.085
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	14
Dann	Benign	0.67
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.62
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.64	T;T;T
M_CAP	Benign	0.0081	T
MetaRNN	Benign	0.080	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	0.50	D;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.27	N;N;N
REVEL	Benign	0.058
Sift	Benign	0.54	T;T;T
Sift4G	Benign	0.78	T;T;T
Polyphen		0.0070	B;B;B
Vest4		0.29
MutPred		0.49		Gain of ubiquitination at R196 (P = 0.0452);.;Gain of ubiquitination at R196 (P = 0.0452);
MVP		0.26
MPC		0.053
ClinPred		0.29	T
GERP RS		1.9
Varity_R		0.062
gMVP		0.39

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: chr10-88418370;