chr3-171066626-C-T

Position:

chr3-171066626-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

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]

TNIK links:

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
TNIK	NM_015028.4 linkuse as main transcript	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 linkuse as main transcript	c.3809G>A	p.Arg1270Gln	missense_variant	31/33	1	NM_015028.4	ENSP00000399511	A1	Q9UKE5-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

151900

Hom.:

Cov.:

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:

AN:

248984

Hom.:

AF XY:

0.0000296

AC XY:

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:

AN:

1461684

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

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:

AN:

151900

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

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 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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Uncertain

0.012

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.27

T;.;.;.;.;.;.;.

Eigen

Pathogenic

0.72

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.86

D;D;D;D;D;D;D;D

MetaSVM

Benign

-1.2

MutationAssessor

Benign

1.1

L;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.86

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over