rs1135401744

Variant names:

• chr2-142918608-G-T
• rs1135401744
• NM_003937.3:c.170-1G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Moderate PS3 PP5_Moderate

The NM_003937.3(KYNU):​c.170-1G>T variant causes a splice acceptor, intron 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 (★). ClinVar reports functional evidence for this variant: "SCV000540921: 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.".

• 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, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.99
• Publications: 3 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 8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08655222 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.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000540921: 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.
• PP5: Variant 2-142918608-G-T is Pathogenic according to our data. Variant chr2-142918608-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 403729.Status of the report is criteria_provided_single_submitter, 1 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.170-1G>T		splice_acceptor intron	N/A	NP_003928.1	Q16719-1
	KYNU	NM_001199241.2		c.170-1G>T		splice_acceptor intron	N/A	NP_001186170.1	Q16719-1
	KYNU	NM_001032998.2		c.170-1G>T		splice_acceptor intron	N/A	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.170-1G>T		splice_acceptor intron	N/A	ENSP00000264170.4	Q16719-1
	KYNU	ENST00000409512.5	TSL:1	c.170-1G>T		splice_acceptor intron	N/A	ENSP00000386731.1	Q16719-1
	KYNU	ENST00000375773.6	TSL:1	c.170-1G>T		splice_acceptor intron	N/A	ENSP00000364928.2	Q16719-2

Frequencies

GnomAD3 genomes AF: 0.0000356 AC: 5 AN: 140558 Hom.: 0 Cov.: 32

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

GnomAD2 exomes AF: 0.000142 AC: 28 AN: 197344 AF XY: 0.000112

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000656 AC: 2 AN: 30468

American (AMR) AF: 0.000262 AC: 9 AN: 34372

Ashkenazi Jewish (ASJ) AF: 0.0000427 AC: 1 AN: 23422

East Asian (EAS) AF: 0.0000554 AC: 2 AN: 36132

South Asian (SAS) AF: 0.0000551 AC: 4 AN: 72604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50512

Middle Eastern (MID) AF: 0.000208 AC: 1 AN: 4798

European-Non Finnish (NFE) AF: 0.0000391 AC: 41 AN: 1048740

Other (OTH) AF: 0.000108 AC: 6 AN: 55560

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 38586

American (AMR) AF: 0.00 AC: 0 AN: 13462

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3372

East Asian (EAS) AF: 0.00 AC: 0 AN: 4902

South Asian (SAS) AF: 0.00 AC: 0 AN: 4384

European-Finnish (FIN) AF: 0.000382 AC: 3 AN: 7860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.0000308 AC: 2 AN: 64974

Other (OTH) AF: 0.00 AC: 0 AN: 1932

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		8.0
GERP RS		5.7
PromoterAI		-0.0043	Neutral
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1135401744; hg19: chr2-143676177;