10-86658061-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_033282.4(OPN4):c.320T>G(p.Met107Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,436 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: OPN4 NM_033282.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.17

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.947

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
OPN4	NM_033282.4	c.320T>G	p.Met107Arg	missense_variant	3/10	ENST00000241891.10
OPN4	NM_001030015.3	c.353T>G	p.Met118Arg	missense_variant	4/11
OPN4	XM_017016955.2	c.353T>G	p.Met118Arg	missense_variant	4/10
OPN4	XM_017016956.2	c.320T>G	p.Met107Arg	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
OPN4	ENST00000241891.10	c.320T>G	p.Met107Arg	missense_variant	3/10	1	NM_033282.4	P1
OPN4	ENST00000372071.7	c.353T>G	p.Met118Arg	missense_variant	4/11	1
OPN4	ENST00000686083.1	n.701T>G		non_coding_transcript_exon_variant	1/3
OPN4	ENST00000690949.1	n.354T>G		non_coding_transcript_exon_variant	4/11

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000159 AC: 4 AN: 251388 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135860

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000217

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461436 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 726994

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

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

Jun 22, 2023

The c.353T>G (p.M118R) alteration is located in exon 4 (coding exon 4) of the OPN4 gene. This alteration results from a T to G substitution at nucleotide position 353, causing the methionine (M) at amino acid position 118 to be replaced by an arginine (R). 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	0.27
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Uncertain	-0.010
Cadd	Uncertain	25
Dann	Uncertain	0.99
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D;D;D
M_CAP	Benign	0.042	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.0040	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.91
MutPred		0.86		Gain of methylation at M118 (P = 0.0173);.;Gain of methylation at M118 (P = 0.0173);
MVP		0.63
MPC		0.31
ClinPred		0.96	D
GERP RS		4.2
Varity_R		0.77
gMVP		0.84

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs749165210; hg19: chr10-88417818;