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GeneBe

7-128772602-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001385125.1(OPN1SW):c.976A>G(p.Thr326Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,614,074 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T326T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

OPN1SW
NM_001385125.1 missense

Scores

19

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.357
Variant links:
Genes affected
OPN1SW (HGNC:1012): (opsin 1, short wave sensitive) This gene belongs to the G-protein coupled receptor 1 family, opsin subfamily. It encodes the blue cone pigment gene which is one of three types of cone photoreceptors responsible for normal color vision. Defects in this gene are the cause of tritan color blindness (tritanopia). Affected individuals lack blue and yellow sensory mechanisms while retaining those for red and green. Defective blue vision is characteristic. [provided by RefSeq, Jul 2008]
CALU (HGNC:1458): (calumenin) The product of this gene is a calcium-binding protein localized in the endoplasmic reticulum (ER) and it is involved in such ER functions as protein folding and sorting. This protein belongs to a family of multiple EF-hand proteins (CERC) that include reticulocalbin, ERC-55, and Cab45 and the product of this gene. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Oct 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.02540043).
BS2
High AC in GnomAdExome4 at 20 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
OPN1SWNM_001385125.1 linkuse as main transcriptc.976A>G p.Thr326Ala missense_variant 5/5 ENST00000249389.3
CALUNM_001219.5 linkuse as main transcriptc.*3435T>C 3_prime_UTR_variant 7/7 ENST00000249364.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
OPN1SWENST00000249389.3 linkuse as main transcriptc.976A>G p.Thr326Ala missense_variant 5/51 NM_001385125.1 P1
CALUENST00000249364.9 linkuse as main transcriptc.*3435T>C 3_prime_UTR_variant 7/71 NM_001219.5 O43852-1
CALUENST00000449187.7 linkuse as main transcriptc.*3435T>C 3_prime_UTR_variant 7/71 P1O43852-2
CALUENST00000542996.7 linkuse as main transcriptc.*3435T>C 3_prime_UTR_variant 8/81 O43852-4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152206
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000192
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251464
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.000163
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:
0.0000137
AC:
20
AN:
1461868
Hom.:
0
Cov.:
31
AF XY:
0.0000124
AC XY:
9
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000126
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.000248
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152206
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74364
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000192
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000478
Bravo
AF:
0.0000189
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 07, 2023The c.985A>G (p.T329A) alteration is located in exon 5 (coding exon 5) of the OPN1SW gene. This alteration results from a A to G substitution at nucleotide position 985, causing the threonine (T) at amino acid position 329 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingInvitaeOct 15, 2023This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 329 of the OPN1SW protein (p.Thr329Ala). This variant is present in population databases (rs750190072, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with OPN1SW-related conditions. ClinVar contains an entry for this variant (Variation ID: 836919). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.071
BayesDel_addAF
Benign
-0.52
T
BayesDel_noAF
Benign
-0.71
CADD
Benign
0.031
DANN
Benign
0.50
DEOGEN2
Benign
0.14
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.050
N
LIST_S2
Benign
0.70
T
M_CAP
Benign
0.0046
T
MetaRNN
Benign
0.025
T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.2
L
MutationTaster
Benign
1.0
N
PrimateAI
Benign
0.24
T
PROVEAN
Benign
-0.41
N
REVEL
Benign
0.036
Sift
Benign
0.29
T
Sift4G
Benign
0.70
T
Polyphen
0.0
B
Vest4
0.086
MutPred
0.18
Loss of glycosylation at T329 (P = 0.0229);
MVP
0.31
MPC
0.15
ClinPred
0.022
T
GERP RS
-2.1
Varity_R
0.019
gMVP
0.091

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

LitVar

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

Other links and lift over

dbSNP: rs750190072; hg19: chr7-128412656; API