Variant 2-142918608-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PVS1_ModeratePP5_Moderate

The NM_003937.3(KYNU):c.170-1G>T variant causes a splice acceptor change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KYNU
NM_003937.3 splice_acceptor

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 7.99

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08583691 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.9, offset of 15, new splice context is: ttcatttgatttatcattAGtga. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.

PP5

Variant 2-142918608-G-T is Pathogenic according to our data. Variant chr2-142918608-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 403729.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-142918608-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KYNU	NM_003937.3 linkuse as main transcript	c.170-1G>T		splice_acceptor_variant		ENST00000264170.9	NP_003928.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KYNU	ENST00000264170.9 linkuse as main transcript	c.170-1G>T		splice_acceptor_variant		1	NM_003937.3	ENSP00000264170	P1	Q16719-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

140558

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000382

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000308

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000142

AC:

AN:

197344

Hom.:

AF XY:

0.000112

AC XY:

AN XY:

106802

show subpopulations

Gnomad AFR exome

AF:

0.0000769

Gnomad AMR exome

AF:

0.0000369

Gnomad ASJ exome

AF:

0.000236

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000219

Gnomad FIN exome

AF:

0.000151

Gnomad NFE exome

AF:

0.000173

Gnomad OTH exome

AF:

0.000216

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000487

AC:

AN:

1356608

Hom.:

Cov.:

AF XY:

0.0000372

AC XY:

AN XY:

672594

show subpopulations

Gnomad4 AFR exome

AF:

0.0000656

Gnomad4 AMR exome

AF:

0.000262

Gnomad4 ASJ exome

AF:

0.0000427

Gnomad4 EAS exome

AF:

0.0000554

Gnomad4 SAS exome

AF:

0.0000551

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000391

Gnomad4 OTH exome

AF:

0.000108

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000356

AC:

AN:

140626

Hom.:

Cov.:

AF XY:

0.0000592

AC XY:

AN XY:

67540

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000382

Gnomad4 NFE

AF:

0.0000308

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Vertebral, cardiac, renal, and limb defects syndrome 2

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Sep 21, 2017

- -

Congenital NAD deficiency disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Embryology Laboratory, Victor Chang Cardiac Research Institute

Dec 23, 2016

This variant was discovered in a consanguineous family of Middle East origin. The patient presented multiple congenital malformations affecting vertebrae, heart, kidney among others. This variant is a protein truncating variant and novel (ExAC MAF 0). The patient is homozygous, while her unaffected parents and four unaffected siblings are either wildtype or heterozygous for this variant. Enzyme assay confirmed that the protein product of this gene variant has lost enzyme activity. Mouse embryos homozygous null for Kynu presented similar phenotype as observed in the patient, and also showed reduced concentration of NAD in the embryonic tissue. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.34

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

1.2

Eigen_PC

Pathogenic

1.0

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

5.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.95

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 16

DS_AL_spliceai

0.98

Position offset: 1

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over