NM_003937.3:c.374-433_435+369del

Variant names:

• chr2-142954375-CTTTTATAAAAGGTGTATTTTAATTTGATGTTAGAAACAACGAACTTTAAAAATGTAATTGGCCTTAATATCTTTTTAGATTCCTTTGAAGATATACTTAGCACAAAAATATGCTCCTTGGGAATTTGACAATTGAGCTGATAATAGGATATATCATTTTTAGTTTACAGGCAAAAGCAAATGCTTCATTATTTTGTTGTTATTTACTACATCATAAAAGAAATTTAATTTTAGCTAGCTGTGTGCATCTAAGTCCAGATATCATTTGATAAAATGAGTCAAGTGGGAAAACTTCCATTTCTTTGTGATGACACATCAAATATGCCCTTATCTCTAAAGACATTAAGAATGATTGAGTGAAGTCTTCCTACTTTGTTTTTTCAGTATCTTTAGACATAGTACAAACATCTAAATTACGATATGTTTATTTTACAGGAGCCAATGAGAAAGAAATAGCCCTAATGAATGCTTTGACTGTAAATTTACATCTTCTAATGGTAAGTTTTCTTTCCCACTAATGTTTAGAACACATTCATTTACAGAATCTGATGTTTTTCTATCTTTAATTCATGAGCTTCTGGGGGTTTACTTATTTAAAAATAAATTGTGAGGTTATTTTCATTTTTACTAGGAAATGCTGGACCATGATATAATAGCTTCTTCCTAATCATGGAAGAGTTGACTCTTGAGAAGAGCTTTAGAATAATGAACAGTTCTTGTCTGGGAAAATAAAGAATAAGAGCCATAATGGGTAAATAGGCAAACTACATGCAAGCCTACAAAACAGTGATGTACAATGCTAGCAAAGCACTGACCTTTTTGGAAAGACAATTTTCTAATGGCTTCAGCAGAGTGAGTTAGTGGA-C
• NM_003937.3:c.374-433_435+369del

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PVS1 PP5

The NM_003937.3(KYNU):​c.374-433_435+369del variant causes a exon loss, splice acceptor, splice donor, splice region, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KYNU NM_003937.3 exon_loss, splice_acceptor, splice_donor, splice_region, intron
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.96
• Publications: 0 publications found

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: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, 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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PP5: Variant 2-142954375-CTTTTATAAAAGGTGTATTTTAATTTGATGTTAGAAACAACGAACTTTAAAAATGTAATTGGCCTTAATATCTTTTTAGATTCCTTTGAAGATATACTTAGCACAAAAATATGCTCCTTGGGAATTTGACAATTGAGCTGATAATAGGATATATCATTTTTAGTTTACAGGCAAAAGCAAATGCTTCATTATTTTGTTGTTATTTACTACATCATAAAAGAAATTTAATTTTAGCTAGCTGTGTGCATCTAAGTCCAGATATCATTTGATAAAATGAGTCAAGTGGGAAAACTTCCATTTCTTTGTGATGACACATCAAATATGCCCTTATCTCTAAAGACATTAAGAATGATTGAGTGAAGTCTTCCTACTTTGTTTTTTCAGTATCTTTAGACATAGTACAAACATCTAAATTACGATATGTTTATTTTACAGGAGCCAATGAGAAAGAAATAGCCCTAATGAATGCTTTGACTGTAAATTTACATCTTCTAATGGTAAGTTTTCTTTCCCACTAATGTTTAGAACACATTCATTTACAGAATCTGATGTTTTTCTATCTTTAATTCATGAGCTTCTGGGGGTTTACTTATTTAAAAATAAATTGTGAGGTTATTTTCATTTTTACTAGGAAATGCTGGACCATGATATAATAGCTTCTTCCTAATCATGGAAGAGTTGACTCTTGAGAAGAGCTTTAGAATAATGAACAGTTCTTGTCTGGGAAAATAAAGAATAAGAGCCATAATGGGTAAATAGGCAAACTACATGCAAGCCTACAAAACAGTGATGTACAATGCTAGCAAAGCACTGACCTTTTTGGAAAGACAATTTTCTAATGGCTTCAGCAGAGTGAGTTAGTGGA-C is Pathogenic according to our data. Variant chr2-142954375-CTTTTATAAAAGGTGTATTTTAATTTGATGTTAGAAACAACGAACTTTAAAAATGTAATTGGCCTTAATATCTTTTTAGATTCCTTTGAAGATATACTTAGCACAAAAATATGCTCCTTGGGAATTTGACAATTGAGCTGATAATAGGATATATCATTTTTAGTTTACAGGCAAAAGCAAATGCTTCATTATTTTGTTGTTATTTACTACATCATAAAAGAAATTTAATTTTAGCTAGCTGTGTGCATCTAAGTCCAGATATCATTTGATAAAATGAGTCAAGTGGGAAAACTTCCATTTCTTTGTGATGACACATCAAATATGCCCTTATCTCTAAAGACATTAAGAATGATTGAGTGAAGTCTTCCTACTTTGTTTTTTCAGTATCTTTAGACATAGTACAAACATCTAAATTACGATATGTTTATTTTACAGGAGCCAATGAGAAAGAAATAGCCCTAATGAATGCTTTGACTGTAAATTTACATCTTCTAATGGTAAGTTTTCTTTCCCACTAATGTTTAGAACACATTCATTTACAGAATCTGATGTTTTTCTATCTTTAATTCATGAGCTTCTGGGGGTTTACTTATTTAAAAATAAATTGTGAGGTTATTTTCATTTTTACTAGGAAATGCTGGACCATGATATAATAGCTTCTTCCTAATCATGGAAGAGTTGACTCTTGAGAAGAGCTTTAGAATAATGAACAGTTCTTGTCTGGGAAAATAAAGAATAAGAGCCATAATGGGTAAATAGGCAAACTACATGCAAGCCTACAAAACAGTGATGTACAATGCTAGCAAAGCACTGACCTTTTTGGAAAGACAATTTTCTAATGGCTTCAGCAGAGTGAGTTAGTGGA-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1695427.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003937.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KYNU	NM_003937.3	MANE Select	c.374-433_435+369del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 5 of 14	NP_003928.1	Q16719-1
	KYNU	NM_001199241.2		c.374-433_435+369del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 6 of 15	NP_001186170.1	Q16719-1
	KYNU	NM_001032998.2		c.374-433_435+369del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 5 of 12	NP_001028170.1	Q16719-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KYNU	ENST00000264170.9	TSL:1 MANE Select	c.374-434_435+368del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 5 of 14	ENSP00000264170.4	Q16719-1
	KYNU	ENST00000409512.5	TSL:1	c.374-434_435+368del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 6 of 15	ENSP00000386731.1	Q16719-1
	KYNU	ENST00000375773.6	TSL:1	c.374-434_435+368del		exon_loss splice_acceptor splice_donor splice_region intron	Exon 5 of 12	ENSP00000364928.2	Q16719-2

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Vertebral, cardiac, renal, and limb defects syndrome 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.0

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr2-143711944;