Genetic Variant NM_003679.5:c.1354C>T (chr1-241592046-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003679.5(KMO):c.1354C>T(p.Arg452Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,613,322 control chromosomes in the GnomAD database, including 35,744 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.16 ( 2374 hom., cov: 31)

Exomes 𝑓: 0.21 ( 33370 hom. )

Consequence

KMO
NM_003679.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.518

Variant links:

Genes affected

KMO (HGNC:6381): (kynurenine 3-monooxygenase) This gene encodes a mitochondrion outer membrane protein that catalyzes the hydroxylation of L-tryptophan metabolite, L-kynurenine, to form L-3-hydroxykynurenine. Studies in yeast identified this gene as a therapeutic target for Huntington disease. [provided by RefSeq, Oct 2011]

KMO links:

OPN3 (HGNC:14007): (opsin 3) Opsins are members of the guanine nucleotide-binding protein (G protein)-coupled receptor superfamily. In addition to the visual opsins, mammals possess several photoreceptive non-visual opsins that are expressed in extraocular tissues. This gene, opsin 3, is strongly expressed in brain and testis and weakly expressed in liver, placenta, heart, lung, skeletal muscle, kidney, and pancreas. The gene may also be expressed in the retina. The protein has the canonical features of a photoreceptive opsin protein. [provided by RefSeq, Jul 2008]

OPN3 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0046176612).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.219 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMO	NM_003679.5 link	c.1354C>T	p.Arg452Cys	missense_variant	Exon 15 of 15	ENST00000366559.9	NP_003670.2	O15229-1A8K693
KMO	NM_001410944.1 link	c.1315C>T	p.Arg439Cys	missense_variant	Exon 15 of 15		NP_001397873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMO	ENST00000366559.9 link	c.1354C>T	p.Arg452Cys	missense_variant	Exon 15 of 15	1	NM_003679.5	ENSP00000355517.4		O15229-1

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23785

AN:

151880

Hom.:

2374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0405

Gnomad AMI

AF:

0.289

Gnomad AMR

AF:

0.132

Gnomad ASJ

AF:

0.186

Gnomad EAS

AF:

0.0553

Gnomad SAS

AF:

0.201

Gnomad FIN

AF:

0.229

Gnomad MID

AF:

0.203

Gnomad NFE

AF:

0.222

Gnomad OTH

AF:

0.172

GnomAD3 exomes

AF:

0.175

AC:

44021

AN:

251020

Hom.:

4478

AF XY:

0.183

AC XY:

24783

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.0348

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.184

Gnomad EAS exome

AF:

0.0528

Gnomad SAS exome

AF:

0.198

Gnomad FIN exome

AF:

0.229

Gnomad NFE exome

AF:

0.219

Gnomad OTH exome

AF:

0.190

GnomAD4 exome

AF:

0.209

AC:

305051

AN:

1461324

Hom.:

33370

Cov.:

AF XY:

0.210

AC XY:

152368

AN XY:

727014

show subpopulations

Gnomad4 AFR exome

AF:

0.0324

Gnomad4 AMR exome

AF:

0.109

Gnomad4 ASJ exome

AF:

0.180

Gnomad4 EAS exome

AF:

0.0580

Gnomad4 SAS exome

AF:

0.200

Gnomad4 FIN exome

AF:

0.226

Gnomad4 NFE exome

AF:

0.225

Gnomad4 OTH exome

AF:

0.191

GnomAD4 genome

AF:

0.156

AC:

23783

AN:

151998

Hom.:

2374

Cov.:

AF XY:

0.157

AC XY:

11637

AN XY:

74270

show subpopulations

Gnomad4 AFR

AF:

0.0404

Gnomad4 AMR

AF:

0.132

Gnomad4 ASJ

AF:

0.186

Gnomad4 EAS

AF:

0.0556

Gnomad4 SAS

AF:

0.201

Gnomad4 FIN

AF:

0.229

Gnomad4 NFE

AF:

0.222

Gnomad4 OTH

AF:

0.170

Alfa

AF:

0.207

Hom.:

8507

Bravo

AF:

0.142

TwinsUK

AF:

0.218

AC:

808

ALSPAC

AF:

0.229

AC:

883

ESP6500AA

AF:

0.0436

AC:

192

ESP6500EA

AF:

0.226

AC:

1945

ExAC

AF:

0.177

AC:

21455

Asia WGS

AF:

0.112

AC:

389

AN:

3478

EpiCase

AF:

0.224

EpiControl

AF:

0.220

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.61

BayesDel_noAF

Benign

-0.51

CADD

Benign

9.8

DANN

Benign

0.78

DEOGEN2

Benign

0.0071

.;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0047

LIST_S2

Benign

0.51

T;T;T

MetaRNN

Benign

0.0046

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

.;N;.

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.63

N;N;N

REVEL

Benign

0.065

Sift

Benign

0.18

T;T;T

Sift4G

Benign

0.18

T;T;T

Polyphen

0.0

.;B;.

Vest4

0.044

MPC

0.47

ClinPred

0.0013

GERP RS

0.34

Varity_R

0.055

gMVP

0.37

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over