3-171085121-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BA1

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 same amino acid change has been previously reported as Likely benignin 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.190

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TNIK
• 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_single_submitter, 1 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/exons	MANE	UniProt
TNIK	NM_015028.4	c.2995G>A	p.Ala999Thr	missense_variant	25/33	ENST00000436636.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TNIK	ENST00000436636.7	c.2995G>A	p.Ala999Thr	missense_variant	25/33	1	NM_015028.4	A1

Frequencies

GnomAD3 genomes AF: 0.0623 AC: 9481 AN: 152070 Hom.: 389 Cov.: 32

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

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.: 30 AF XY: 0.0798 AC XY: 57502 AN XY: 720940

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.: 32 AF XY: 0.0597 AC XY: 4444 AN XY: 74422

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: 53

ESP6500EA AF: 0.0875 AC: 721

ExAC AF: 0.0647 AC: 7814

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, autosomal recessive 54 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

May 18, 2021

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.58	T
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	N
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	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P;P;P
PrimateAI	Benign	0.42	T
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	T
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

Other links and lift over

dbSNP: rs17857452; hg19: chr3-170802910; COSMIC: COSV52678169; COSMIC: COSV52678169;