Genetic Variant TNIK:p.Ala999Thr (chr3-171085121-C-T) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_015028.4(TNIK):c.2995G>A(p.Ala999Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0783 in 1,603,824 control chromosomes in the GnomAD database, including 5,505 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A999V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.062 ( 390 hom., cov: 32)

Exomes 𝑓: 0.080 ( 5115 hom. )

Consequence

TNIK
NM_015028.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.190

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0015702248).

BP6

Variant 3-171085121-C-T is Benign according to our data. Variant chr3-171085121-C-T is described in ClinVar as [Benign]. Clinvar id is 1098861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNIK	NM_015028.4 link	c.2995G>A	p.Ala999Thr	missense_variant	Exon 25 of 33	ENST00000436636.7	NP_055843.1	Q9UKE5-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNIK	ENST00000436636.7 link	c.2995G>A	p.Ala999Thr	missense_variant	Exon 25 of 33	1	NM_015028.4	ENSP00000399511.2		Q9UKE5-1

Frequencies

GnomAD3 genomes

AF:

0.0623

AC:

9481

AN:

152070

Hom.:

389

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0154

Gnomad AMI

AF:

0.143

Gnomad AMR

AF:

0.0703

Gnomad ASJ

AF:

0.109

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0599

Gnomad FIN

AF:

0.0518

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0917

Gnomad OTH

AF:

0.0703

GnomAD3 exomes

AF:

0.0681

AC:

15976

AN:

234694

Hom.:

660

AF XY:

0.0695

AC XY:

8812

AN XY:

126746

show subpopulations

Gnomad AFR exome

AF:

0.0142

Gnomad AMR exome

AF:

0.0706

Gnomad ASJ exome

AF:

0.120

Gnomad EAS exome

AF:

0.000524

Gnomad SAS exome

AF:

0.0514

Gnomad FIN exome

AF:

0.0561

Gnomad NFE exome

AF:

0.0869

Gnomad OTH exome

AF:

0.0855

GnomAD4 exome

AF:

0.0800

AC:

116160

AN:

1451636

Hom.:

5115

Cov.:

AF XY:

0.0798

AC XY:

57502

AN XY:

720940

show subpopulations

Gnomad4 AFR exome

AF:

0.0139

Gnomad4 AMR exome

AF:

0.0716

Gnomad4 ASJ exome

AF:

0.117

Gnomad4 EAS exome

AF:

0.000456

Gnomad4 SAS exome

AF:

0.0529

Gnomad4 FIN exome

AF:

0.0571

Gnomad4 NFE exome

AF:

0.0875

Gnomad4 OTH exome

AF:

0.0785

GnomAD4 genome

AF:

0.0623

AC:

9480

AN:

152188

Hom.:

390

Cov.:

AF XY:

0.0597

AC XY:

4444

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.0154

Gnomad4 AMR

AF:

0.0701

Gnomad4 ASJ

AF:

0.109

Gnomad4 EAS

AF:

0.000578

Gnomad4 SAS

AF:

0.0595

Gnomad4 FIN

AF:

0.0518

Gnomad4 NFE

AF:

0.0917

Gnomad4 OTH

AF:

0.0695

Alfa

AF:

0.0853

Hom.:

943

Bravo

AF:

0.0616

TwinsUK

AF:

0.0850

AC:

315

ALSPAC

AF:

0.0882

AC:

340

ESP6500AA

AF:

0.0139

AC:

ESP6500EA

AF:

0.0875

AC:

721

ExAC

AF:

0.0647

AC:

7814

Asia WGS

AF:

0.0290

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Intellectual disability, autosomal recessive 54

Benign:1

May 18, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.53

CADD

Benign

5.5

DANN

Benign

0.23

DEOGEN2

Benign

0.061

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

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.043

LIST_S2

Benign

0.67

T;T;T;T;T;T;T;T

MetaRNN

Benign

0.0016

T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.2

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

PrimateAI

Benign

0.42

PROVEAN

Benign

0.040

N;N;N;N;N;N;N;N

REVEL

Benign

0.092

Sift

Benign

0.83

T;T;T;T;T;T;T;T

Sift4G

Benign

0.72

T;T;T;T;T;T;T;T

Polyphen

0.066

B;B;B;B;B;B;B;B

Vest4

0.024

MPC

0.32

ClinPred

0.00032

GERP RS

0.14

Varity_R

0.017

gMVP

0.29

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