1-241555613-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003679.5(KMO):ā€‹c.314A>Gā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 7.2e-7 ( 0 hom. )

Consequence

KMO
NM_003679.5 missense, splice_region

Scores

5
14
Splicing: ADA: 0.001412
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.70
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

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
KMONM_003679.5 linkc.314A>G p.Tyr105Cys missense_variant, splice_region_variant 5/15 ENST00000366559.9 NP_003670.2 O15229-1A8K693
KMONM_001410944.1 linkc.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
KMOENST00000366559.9 linkc.314A>G p.Tyr105Cys missense_variant, splice_region_variant 5/151 NM_003679.5 ENSP00000355517.4 O15229-1

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
show subpopulations
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
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsDec 06, 2024The 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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1661583124; hg19: chr1-241718913; API