1-241555613-A-G

Position:

• chr1-241555613-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.314A>G​(p.Tyr105Cys) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000072 in 1,389,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: KMO NM_003679.5 missense, splice_region
• Scores: Splicing: ADA: 0.001412
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.70

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2255449).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMO	NM_003679.5	c.314A>G	p.Tyr105Cys	missense_variant, splice_region_variant	5/15	ENST00000366559.9	NP_003670.2
KMO	NM_001410944.1	c.314A>G	p.Tyr105Cys	missense_variant, splice_region_variant	5/15		NP_001397873.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMO	ENST00000366559.9	c.314A>G	p.Tyr105Cys	missense_variant, splice_region_variant	5/15	1	NM_003679.5	ENSP00000355517.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.20e-7 AC: 1 AN: 1389370 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 695386

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.54e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 06, 2024

The c.314A>G (p.Y105C) alteration is located in exon 5 (coding exon 5) of the KMO gene. This alteration results from a A to G substitution at nucleotide position 314, causing the tyrosine (Y) at amino acid position 105 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	0.10
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0094	.;T;.
Eigen	Benign	-0.22
Eigen_PC	Benign	-0.067
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.23	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Benign	0.17
Sift	Benign	0.59	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		0.28	B;B;.
Vest4		0.46
MutPred		0.55		Gain of methylation at K102 (P = 0.0529);Gain of methylation at K102 (P = 0.0529);Gain of methylation at K102 (P = 0.0529);
MVP		0.72
MPC		0.48
ClinPred		0.64	D
GERP RS		4.4
Varity_R		0.23
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0014
dbscSNV1_RF	Benign	0.028
SpliceAI score (max)		0.050		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: rs1661583124; hg19: chr1-241718913;