2-142927737-TGTAG-T
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PM2PP3_ModeratePP5_Moderate
The NM_003937.3(KYNU):c.373_373+3del variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.00000125 in 1,605,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
KYNU
NM_003937.3 frameshift, splice_region
NM_003937.3 frameshift, splice_region
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.64
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 2-142927737-TGTAG-T is Pathogenic according to our data. Variant chr2-142927737-TGTAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2632261.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
KYNU | NM_003937.3 | c.373_373+3del | frameshift_variant, splice_region_variant | 4/14 | ENST00000264170.9 | NP_003928.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
KYNU | ENST00000264170.9 | c.373_373+3del | frameshift_variant, splice_region_variant | 4/14 | 1 | NM_003937.3 | ENSP00000264170 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.88e-7 AC: 1AN: 1452834Hom.: 0 AF XY: 0.00000138 AC XY: 1AN XY: 723460
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152180Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74350
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ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
KYNU-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Jun 21, 2023 | The KYNU c.373_373+3delGGTA variant is predicted to result in a deletion affecting a canonical splice site. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Frameshift variants in KYNU are expected to be pathogenic. This variant is interpreted as likely pathogenic. - |
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DS_DL_spliceai
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at