NM_003679.5:c.712T>C

Variant names:

• chr1-241566515-T-C
• NM_003679.5:c.712T>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003679.5(KMO):​c.712T>C​(p.Phe238Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMO NM_003679.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.96
• 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.898

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.712T>C	p.Phe238Leu	missense	Exon 9 of 15	NP_003670.2	O15229-1
	KMO	NM_001410944.1		c.712T>C	p.Phe238Leu	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.712T>C	p.Phe238Leu	missense	Exon 9 of 15	ENSP00000355517.4	O15229-1
	KMO	ENST00000366558.7	TSL:1	c.712T>C	p.Phe238Leu	missense	Exon 9 of 15	ENSP00000355516.3	O15229-2
	KMO	ENST00000881617.1		c.712T>C	p.Phe238Leu	missense	Exon 9 of 16	ENSP00000551676.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	29
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.22	T
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Pathogenic	3.5	M
PhyloP100		8.0
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.52
Sift	Uncertain	0.0060	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.98	D
Vest4		0.82
MutPred		0.75		Loss of sheet (P = 0.0315)
MVP		0.66
MPC		1.2
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.89
gMVP		0.93
Mutation Taster		=15/85	disease causing

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

hg19: chr1-241729815;