rs1135401744

chr2-142918608-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Moderate PP3_Strong PP5_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. 2/2 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

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Splicing variant, 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.
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
KYNU	NM_003937.3	c.170-1G>T		splice_acceptor_variant		ENST00000264170.9

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.00 AC: 5 AN: 140558 Hom.: 0 Cov.: 32 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: 28 AN: 197344 Hom.: 0 AF XY: 0.000112 AC XY: 12 AN XY: 106802

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: 66 AN: 1356608 Hom.: 0 Cov.: 34 AF XY: 0.0000372 AC XY: 25 AN XY: 672594

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: 5 AN: 140626 Hom.: 0 Cov.: 32 AF XY: 0.0000592 AC XY: 4 AN XY: 67540

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

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	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	36
Dann	Uncertain	0.99
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
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

Other links and lift over

dbSNP: rs1135401744; hg19: chr2-143676177;