NM_003937.3:c.592A>G

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

The NM_003937.3(KYNU):c.592A>G(p.Thr198Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000411 in 1,461,408 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T198N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

KYNU
NM_003937.3 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 6.50

Publications

7 publications found

Variant links:

Genes affected

KYNU (HGNC:6469): (kynureninase) Kynureninase is a pyridoxal-5'-phosphate (pyridoxal-P) dependent enzyme that catalyzes the cleavage of L-kynurenine and L-3-hydroxykynurenine into anthranilic and 3-hydroxyanthranilic acids, respectively. Kynureninase is involved in the biosynthesis of NAD cofactors from tryptophan through the kynurenine pathway. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2010]

KYNU Gene-Disease associations (from GenCC):

vertebral, cardiac, renal, and limb defects syndrome 2
Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), ClinGen
encephalopathy due to hydroxykynureninuria
Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
congenital vertebral-cardiac-renal anomalies syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

KYNU links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.868

PP5

Variant 2-142960633-A-G is Pathogenic according to our data. Variant chr2-142960633-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 160355.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KYNU	NM_003937.3 link	c.592A>G	p.Thr198Ala	missense_variant	Exon 8 of 14	ENST00000264170.9	NP_003928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KYNU	ENST00000264170.9 link	c.592A>G	p.Thr198Ala	missense_variant	Exon 8 of 14	1	NM_003937.3	ENSP00000264170.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000159

AC:

AN:

251006

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000411

AC:

AN:

1461408

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33468

American (AMR)

AF:

0.0000671

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39674

South Asian (SAS)

AF:

0.00

AC:

AN:

86240

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111670

Other (OTH)

AF:

0.0000331

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hydroxykynureninuria

Pathogenic:1

Apr 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0057

BayesDel_noAF

Uncertain

0.0

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Uncertain

0.44

T;.;T;.

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.87

.;D;D;T

M_CAP

Benign

0.035

MetaRNN

Pathogenic

0.87

D;D;D;D

MetaSVM

Benign

-0.33

MutationAssessor

Uncertain

2.2

M;M;M;.

PhyloP100

6.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-2.5

D;N;D;.

REVEL

Uncertain

0.55

Sift

Benign

0.15

T;T;T;.

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0010

B;.;B;.

Vest4

0.74

MutPred

0.78

Loss of phosphorylation at T198 (P = 0.0649);Loss of phosphorylation at T198 (P = 0.0649);Loss of phosphorylation at T198 (P = 0.0649);.;

MVP

0.95

MPC

0.040

ClinPred

0.22

GERP RS

2.8

Varity_R

0.12

gMVP

0.69

Mutation Taster

=19/81

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over