1-241566563-G-C

Variant names:

• chr1-241566563-G-C
• rs761201360
• NM_003679.5:c.760G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003679.5(KMO):​c.760G>C​(p.Val254Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,461,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. V254I) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: KMO NM_003679.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.50
• Publications: 0 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]

KMO Gene-Disease associations (from GenCC):

• pellagra

  Inheritance: AR Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.034627825).

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.760G>C	p.Val254Leu	missense	Exon 9 of 15	NP_003670.2	O15229-1
	KMO	NM_001410944.1		c.760G>C	p.Val254Leu	missense	Exon 9 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.760G>C	p.Val254Leu	missense	Exon 9 of 15	ENSP00000355517.4	O15229-1
	KMO	ENST00000366558.7	TSL:1	c.760G>C	p.Val254Leu	missense	Exon 9 of 15	ENSP00000355516.3	O15229-2
	KMO	ENST00000881617.1		c.760G>C	p.Val254Leu	missense	Exon 9 of 16	ENSP00000551676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251032 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS 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: 0.00000411 AC: 6 AN: 1461210 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 726928

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.0000696 AC: 6 AN: 86210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111468

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	4.8
DANN	Benign	0.39
DEOGEN2	Benign	0.0057	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.38	N
LIST_S2	Benign	0.64	T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-1.5	N
PhyloP100		1.5
PrimateAI	Benign	0.27	T
PROVEAN	Benign	2.3	N
REVEL	Benign	0.054
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.15
MutPred		0.43		Loss of helix (P = 0.0626)
MVP		0.13
MPC		0.34
ClinPred		0.020	T
GERP RS		3.0
Varity_R		0.070
gMVP		0.56
Mutation Taster		=91/9	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs761201360; hg19: chr1-241729863;