Genetic Variant TNIK:p.Pro1175Pro (chr3-171071247-C-T) – ACMG Classification: Likely_benign (-5 pts)

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_ModerateBP6_ModerateBP7

The NM_015028.4(TNIK):c.3525G>A(p.Pro1175Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000106 in 1,603,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

TNIK
NM_015028.4 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: -0.998

Publications

3 publications found

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 Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 54
Inheritance: AR, Unknown Classification: MODERATE, LIMITED Submitted by: Illumina, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TNIK links:

ENSG00000286856 (HGNC:):

ENSG00000286856 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 3-171071247-C-T is Benign according to our data. Variant chr3-171071247-C-T is described in ClinVar as Benign. ClinVar VariationId is 747587.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.998 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015028.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNIK	NM_015028.4	MANE Select	c.3525G>A	p.Pro1175Pro	synonymous	Exon 29 of 33	NP_055843.1	Q9UKE5-1
TNIK	NM_001161560.3		c.3501G>A	p.Pro1167Pro	synonymous	Exon 28 of 32	NP_001155032.1	Q9UKE5-4
TNIK	NM_001161561.3		c.3438G>A	p.Pro1146Pro	synonymous	Exon 28 of 32	NP_001155033.1	Q9UKE5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TNIK	ENST00000436636.7	TSL:1 MANE Select	c.3525G>A	p.Pro1175Pro	synonymous	Exon 29 of 33	ENSP00000399511.2	Q9UKE5-1
TNIK	ENST00000284483.12	TSL:1	c.3501G>A	p.Pro1167Pro	synonymous	Exon 28 of 32	ENSP00000284483.8	Q9UKE5-4
TNIK	ENST00000357327.9	TSL:1	c.3438G>A	p.Pro1146Pro	synonymous	Exon 28 of 32	ENSP00000349880.5	Q9UKE5-2

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00135

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000219

AC:

AN:

236954

AF XY:

0.000211

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000304

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00252

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000557

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000109

AC:

158

AN:

1451648

Hom.:

Cov.:

AF XY:

0.000105

AC XY:

AN XY:

721016

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33258

American (AMR)

AF:

0.0000230

AC:

AN:

43450

Ashkenazi Jewish (ASJ)

AF:

0.0000388

AC:

AN:

25774

East Asian (EAS)

AF:

0.00210

AC:

AN:

39486

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83594

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52550

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000596

AC:

AN:

1107788

Other (OTH)

AF:

0.000100

AC:

AN:

60010

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152168

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41512

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3468

East Asian (EAS)

AF:

0.00135

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10580

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

67996

Other (OTH)

AF:

0.00

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000565

Hom.:

Bravo

AF:

0.000132

Asia WGS

AF:

0.00116

AC:

AN:

3472

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

TNIK-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

4.8

(source)

DANN

Benign

0.57

PhyloP100

-1.0

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over