rs1053230

Positions:

• chr1-241592046-C-T

Variant summary

Our verdict is Benign. Variant got -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. 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 same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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

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/exons	MANE	Protein	UniProt
KMO	NM_003679.5	c.1354C>T	p.Arg452Cys	missense_variant	15/15	ENST00000366559.9	NP_003670.2
KMO	NM_001410944.1	c.1315C>T	p.Arg439Cys	missense_variant	15/15		NP_001397873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMO	ENST00000366559.9	c.1354C>T	p.Arg452Cys	missense_variant	15/15	1	NM_003679.5	ENSP00000355517	P2

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

GnomAD3 exomes AF: 0.175 AC: 44021 AN: 251020 Hom.: 4478 AF XY: 0.183 AC XY: 24783 AN XY: 135640

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

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.: 31 AF XY: 0.157 AC XY: 11637 AN XY: 74270

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	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;T;T
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	.;N;.
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.24	T
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	T
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

Other links and lift over

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