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3-171085120-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_015028.4(TNIK):c.2996C>T(p.Ala999Val) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A999T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

TNIK
NM_015028.4 missense, splice_region

Scores

1
1
17
Splicing: ADA: 0.1234
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.73
Variant links:
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant where missense usually causes diseases, TNIK
BP4
Computational evidence support a benign effect (MetaRNN=0.12479207).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
TNIKNM_015028.4 linkuse as main transcriptc.2996C>T p.Ala999Val missense_variant, splice_region_variant 25/33 ENST00000436636.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
TNIKENST00000436636.7 linkuse as main transcriptc.2996C>T p.Ala999Val missense_variant, splice_region_variant 25/331 NM_015028.4 A1Q9UKE5-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
30
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 14, 2023The c.2996C>T (p.A999V) alteration is located in exon 25 (coding exon 25) of the TNIK gene. This alteration results from a C to T substitution at nucleotide position 2996, causing the alanine (A) at amino acid position 999 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.079
T
BayesDel_noAF
Benign
-0.35
Cadd
Benign
23
Dann
Benign
0.29
DEOGEN2
Benign
0.056
T;.;.;.;.;.;.;.
Eigen
Benign
-0.22
Eigen_PC
Benign
-0.051
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.95
D;D;D;D;D;D;D;D
M_CAP
Benign
0.020
T
MetaRNN
Benign
0.12
T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
1.2
L;.;.;.;.;.;.;.
MutationTaster
Benign
0.95
N;N;N;N;N;N;N;N;N;N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-0.19
N;N;N;N;N;N;N;N
REVEL
Benign
0.13
Sift
Benign
0.52
T;T;T;T;T;T;T;T
Sift4G
Benign
0.55
T;T;T;T;T;T;T;T
Polyphen
0.035
B;B;B;B;B;B;B;B
Vest4
0.26
MutPred
0.24
Gain of loop (P = 0.0435);.;.;.;.;.;.;.;
MVP
0.44
MPC
0.33
ClinPred
0.63
D
GERP RS
5.4
Varity_R
0.068
gMVP
0.27

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.12
dbscSNV1_RF
Benign
0.29
SpliceAI score (max)
0.030
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-170802909; API