chr1-241592023-A-G

Position:

• chr1-241592023-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003679.5(KMO):​c.1331A>G​(p.Tyr444Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMO NM_003679.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.150

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:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07713351).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMO	NM_003679.5	c.1331A>G	p.Tyr444Cys	missense_variant	15/15	ENST00000366559.9	NP_003670.2
KMO	NM_001410944.1	c.1292A>G	p.Tyr431Cys	missense_variant	15/15		NP_001397873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMO	ENST00000366559.9	c.1331A>G	p.Tyr444Cys	missense_variant	15/15	1	NM_003679.5	ENSP00000355517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Jan 26, 2022

The c.1331A>G (p.Y444C) alteration is located in exon 15 (coding exon 15) of the KMO gene. This alteration results from a A to G substitution at nucleotide position 1331, causing the tyrosine (Y) at amino acid position 444 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	0.058
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	5.1
DANN	Benign	0.59
DEOGEN2	Benign	0.022	.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.44	T;T;T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.077	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	.;L;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.068
Sift	Benign	0.16	T;T;T
Sift4G	Benign	0.18	T;T;T
Polyphen		0.0	.;B;.
Vest4		0.073
MutPred		0.47		.;Gain of loop (P = 0.0079);.;
MVP		0.18
MPC		0.43
ClinPred		0.026	T
GERP RS		0.74
Varity_R		0.067
gMVP		0.35

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-241755325; COSMIC: COSV104405507; COSMIC: COSV104405507;