chr1-241565006-A-G

Position:

• chr1-241565006-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000366559.9(KMO):​c.635A>G​(p.Tyr212Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KMO ENST00000366559.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.77

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMO	NM_003679.5	c.635A>G	p.Tyr212Cys	missense_variant	8/15	ENST00000366559.9	NP_003670.2
KMO	NM_001410944.1	c.635A>G	p.Tyr212Cys	missense_variant	8/15		NP_001397873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMO	ENST00000366559.9	c.635A>G	p.Tyr212Cys	missense_variant	8/15	1	NM_003679.5	ENSP00000355517	P2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 31

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2023

The c.635A>G (p.Y212C) alteration is located in exon 8 (coding exon 8) of the KMO gene. This alteration results from a A to G substitution at nucleotide position 635, causing the tyrosine (Y) at amino acid position 212 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;.
Eigen	Benign	-0.075
Eigen_PC	Benign	0.042
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.45	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-6.6	D;D;D
REVEL	Benign	0.15
Sift	Benign	0.076	T;T;T
Sift4G	Benign	0.14	T;T;T
Polyphen		0.24	B;B;.
Vest4		0.55
MutPred		0.70		Loss of phosphorylation at Y212 (P = 0.0255);Loss of phosphorylation at Y212 (P = 0.0255);Loss of phosphorylation at Y212 (P = 0.0255);
MVP		0.65
MPC		0.81
ClinPred		0.95	D
GERP RS		3.3
Varity_R		0.47
gMVP		0.90

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: rs1037960306; hg19: chr1-241728306; COSMIC: COSV63805678; COSMIC: COSV63805678;