3-171066626-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate
The NM_015028.4(TNIK):c.3809G>A(p.Arg1270Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,584 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000096 ( 0 hom. )
Consequence
TNIK
NM_015028.4 missense
NM_015028.4 missense
Scores
8
4
7
Clinical Significance
Conservation
PhyloP100: 7.91
Genes affected
TNIK (HGNC:30765): (TRAF2 and NCK interacting kinase) Wnt signaling plays important roles in carcinogenesis and embryonic development. The protein encoded by this gene is a serine/threonine kinase that functions as an activator of the Wnt signaling pathway. Mutations in this gene are associated with an autosomal recessive form of cognitive disability. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Jul 2017]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 5 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), TNIK. . Gene score misZ 4.1047 (greater than the threshold 3.09). Trascript score misZ 4.5811 (greater than threshold 3.09). GenCC has associacion of gene with autosomal recessive non-syndromic intellectual disability, intellectual disability, autosomal recessive 54.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.863
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TNIK | NM_015028.4 | c.3809G>A | p.Arg1270Gln | missense_variant | 31/33 | ENST00000436636.7 | NP_055843.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TNIK | ENST00000436636.7 | c.3809G>A | p.Arg1270Gln | missense_variant | 31/33 | 1 | NM_015028.4 | ENSP00000399511 | A1 |
Frequencies
GnomAD3 genomes AF: 0.0000132 AC: 2AN: 151900Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000201 AC: 5AN: 248984Hom.: 0 AF XY: 0.0000296 AC XY: 4AN XY: 135048
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GnomAD4 exome AF: 0.00000958 AC: 14AN: 1461684Hom.: 0 Cov.: 33 AF XY: 0.0000110 AC XY: 8AN XY: 727126
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GnomAD4 genome AF: 0.0000132 AC: 2AN: 151900Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 74180
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
TNIK-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | May 23, 2023 | The TNIK c.3809G>A variant is predicted to result in the amino acid substitution p.Arg1270Gln. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0083% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/3-170784415-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.;.;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;D
M_CAP
Benign
T
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D
MetaSVM
Benign
T
MutationAssessor
Benign
L;.;.;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D;D;D;D;D
REVEL
Uncertain
Sift
Benign
T;T;T;T;T;T;T;T
Sift4G
Benign
T;T;T;T;T;T;T;T
Polyphen
D;D;D;D;P;D;D;P
Vest4
MutPred
Gain of glycosylation at T1272 (P = 0.0185);.;.;.;.;.;.;.;
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at