10-86658061-T-G

Variant names:

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.17

Variant links:

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]

OPN4 links:

ENSG00000289258 (HGNC:):

ENSG00000289258 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 rank	MANE	Protein	UniProt
OPN4	NM_033282.4 link	c.320T>G	p.Met107Arg	missense_variant	Exon 3 of 10	ENST00000241891.10	NP_150598.1	Q9UHM6-1
OPN4	NM_001030015.3 link	c.353T>G	p.Met118Arg	missense_variant	Exon 4 of 11		NP_001025186.1	Q9UHM6-2
OPN4	XM_017016955.2 link	c.353T>G	p.Met118Arg	missense_variant	Exon 4 of 10		XP_016872444.1
OPN4	XM_017016956.2 link	c.320T>G	p.Met107Arg	missense_variant	Exon 3 of 9		XP_016872445.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
OPN4	ENST00000241891.10 link	c.320T>G	p.Met107Arg	missense_variant	Exon 3 of 10	1	NM_033282.4	ENSP00000241891.5		Q9UHM6-1
ENSG00000289258	ENST00000443292.2 link	c.353T>G	p.Met118Arg	missense_variant	Exon 4 of 18	1		ENSP00000393132.2		C9JWU6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251388

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135860

show subpopulations

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:

AN:

1461436

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

726994

show subpopulations

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.:

Bravo

AF:

0.0000189

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

BayesDel_noAF

Uncertain

-0.010

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.31

.;T;.

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.94

D;D;D

M_CAP

Benign

0.042

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Benign

-0.84

MutationAssessor

Uncertain

2.6

.;M;.

PrimateAI

Uncertain

0.51

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over