rs1053230

Variant names:

• chr1-241592046-C-T
• rs1053230
• NM_003679.5:c.1354C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

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. 15/21 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R452S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.16 (2374 hom., cov: 31)
  • Exomes 𝑓: 0.21 (33370 hom.)
• Consequence: KMO NM_003679.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.518
• Publications: 49 publications found

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]

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]

ACMG classification

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003679.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMO	NM_003679.5	MANE Select	c.1354C>T	p.Arg452Cys	missense	Exon 15 of 15	NP_003670.2	O15229-1
	KMO	NM_001410944.1		c.1315C>T	p.Arg439Cys	missense	Exon 15 of 15	NP_001397873.1	O15229-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMO	ENST00000366559.9	TSL:1 MANE Select	c.1354C>T	p.Arg452Cys	missense	Exon 15 of 15	ENSP00000355517.4	O15229-1
	KMO	ENST00000366558.7	TSL:1	c.1315C>T	p.Arg439Cys	missense	Exon 15 of 15	ENSP00000355516.3	O15229-2
	KMO	ENST00000881617.1		c.1417C>T	p.Arg473Cys	missense	Exon 16 of 16	ENSP00000551676.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23785 AN: 151880 Hom.: 2374 Cov.: 31

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

GnomAD2 exomes AF: 0.175 AC: 44021 AN: 251020 AF XY: 0.183

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 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.: 32 AF XY: 0.210 AC XY: 152368 AN XY: 727014

African (AFR) AF: 0.0324 AC: 1085 AN: 33466

American (AMR) AF: 0.109 AC: 4870 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.180 AC: 4702 AN: 26132

East Asian (EAS) AF: 0.0580 AC: 2300 AN: 39682

South Asian (SAS) AF: 0.200 AC: 17276 AN: 86250

European-Finnish (FIN) AF: 0.226 AC: 12093 AN: 53400

Middle Eastern (MID) AF: 0.200 AC: 1155 AN: 5762

European-Non Finnish (NFE) AF: 0.225 AC: 250042 AN: 1111528

Other (OTH) AF: 0.191 AC: 11528 AN: 60384

GnomAD4 genome AF: 0.156 AC: 23783 AN: 151998 Hom.: 2374 Cov.: 31 AF XY: 0.157 AC XY: 11637 AN XY: 74270

African (AFR) AF: 0.0404 AC: 1675 AN: 41492

American (AMR) AF: 0.132 AC: 2007 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 644 AN: 3468

East Asian (EAS) AF: 0.0556 AC: 287 AN: 5162

South Asian (SAS) AF: 0.201 AC: 966 AN: 4798

European-Finnish (FIN) AF: 0.229 AC: 2420 AN: 10556

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.222 AC: 15103 AN: 67954

Other (OTH) AF: 0.170 AC: 359 AN: 2108

Alfa AF: 0.196 Hom.: 12073

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 v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.61	T
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	N
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.52
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.065
Sift	Benign	0.18	T
Sift4G	Benign	0.18	T
Polyphen		0.0	B
Vest4		0.044
MPC		0.47
ClinPred		0.0013	T
GERP RS		0.34
Varity_R		0.055
gMVP		0.37
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1053230; hg19: chr1-241755348; COSMIC: COSV59364636; COSMIC: COSV59364636;