3-171066626-C-T

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

Scores

8
4
7

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.91
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]

Genome browser will be placed here

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
TNIKNM_015028.4 linkuse as main transcriptc.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
TNIKENST00000436636.7 linkuse as main transcriptc.3809G>A p.Arg1270Gln missense_variant 31/331 NM_015028.4 ENSP00000399511 A1Q9UKE5-1

Frequencies

GnomAD3 genomes
AF:
0.0000132
AC:
2
AN:
151900
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.0000242
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248984
Hom.:
0
AF XY:
0.0000296
AC XY:
4
AN XY:
135048
show subpopulations
Gnomad AFR exome
AF:
0.0000646
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000355
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000958
AC:
14
AN:
1461684
Hom.:
0
Cov.:
33
AF XY:
0.0000110
AC XY:
8
AN XY:
727126
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.0000116
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000899
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000132
AC:
2
AN:
151900
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74180
show subpopulations
Gnomad4 AFR
AF:
0.0000242
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.0000248
AC:
3
EpiCase
AF:
0.000109
EpiControl
AF:
0.00

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 submitterclinical testingPreventionGenetics, part of Exact SciencesMay 23, 2023The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.88
BayesDel_addAF
Uncertain
0.012
T
BayesDel_noAF
Uncertain
-0.040
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.27
T;.;.;.;.;.;.;.
Eigen
Pathogenic
0.72
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Pathogenic
0.99
D;D;D;D;D;D;D;D
M_CAP
Benign
0.012
T
MetaRNN
Pathogenic
0.86
D;D;D;D;D;D;D;D
MetaSVM
Benign
-1.2
T
MutationAssessor
Benign
1.1
L;.;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D;D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
0.86
D
PROVEAN
Uncertain
-3.4
D;D;D;D;D;D;D;D
REVEL
Uncertain
0.48
Sift
Benign
0.14
T;T;T;T;T;T;T;T
Sift4G
Benign
0.084
T;T;T;T;T;T;T;T
Polyphen
0.99
D;D;D;D;P;D;D;P
Vest4
0.78
MutPred
0.78
Gain of glycosylation at T1272 (P = 0.0185);.;.;.;.;.;.;.;
MVP
0.49
MPC
2.4
ClinPred
0.91
D
GERP RS
6.0
Varity_R
0.48
gMVP
0.52

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs764331012; hg19: chr3-170784415; COSMIC: COSV52678048; COSMIC: COSV52678048; API