Genetic Variant NM_015028.4:c.1222-108A>C (chr3-171140617-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_015028.4(TNIK):c.1222-108A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.744 in 955,710 control chromosomes in the GnomAD database, including 265,984 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.75 ( 42655 hom., cov: 31)

Exomes 𝑓: 0.74 ( 223329 hom. )

Consequence

TNIK
NM_015028.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.109

Publications

5 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):

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

TNIK links:

LOC105374216 (HGNC:):

LOC105374216 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.89).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.744 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNIK	NM_015028.4 link	c.1222-108A>C		intron_variant	Intron 12 of 32	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.1222-108A>C		intron_variant	Intron 12 of 32	1	NM_015028.4	ENSP00000399511.2		Q9UKE5-1

Frequencies

GnomAD3 genomes

AF:

0.747

AC:

113440

AN:

151856

Hom.:

42621

Cov.:

show subpopulations

Gnomad AFR

AF:

0.742

Gnomad AMI

AF:

0.878

Gnomad AMR

AF:

0.751

Gnomad ASJ

AF:

0.733

Gnomad EAS

AF:

0.558

Gnomad SAS

AF:

0.721

Gnomad FIN

AF:

0.850

Gnomad MID

AF:

0.723

Gnomad NFE

AF:

0.750

Gnomad OTH

AF:

0.707

GnomAD4 exome

AF:

0.743

AC:

597493

AN:

803736

Hom.:

223329

AF XY:

0.741

AC XY:

313918

AN XY:

423778

show subpopulations

African (AFR)

AF:

0.740

AC:

15066

AN:

20362

American (AMR)

AF:

0.782

AC:

31012

AN:

39654

Ashkenazi Jewish (ASJ)

AF:

0.741

AC:

15249

AN:

20582

East Asian (EAS)

AF:

0.572

AC:

20644

AN:

36086

South Asian (SAS)

AF:

0.709

AC:

49291

AN:

69480

European-Finnish (FIN)

AF:

0.838

AC:

32756

AN:

39092

Middle Eastern (MID)

AF:

0.751

AC:

3323

AN:

4422

European-Non Finnish (NFE)

AF:

0.750

AC:

401575

AN:

535320

Other (OTH)

AF:

0.738

AC:

28577

AN:

38738

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

7460

14919

22379

29838

37298

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6178

12356

18534

24712

30890

<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:

0.747

AC:

113529

AN:

151974

Hom.:

42655

Cov.:

AF XY:

0.749

AC XY:

55618

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.742

AC:

30732

AN:

41404

American (AMR)

AF:

0.752

AC:

11488

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.733

AC:

2539

AN:

3466

East Asian (EAS)

AF:

0.557

AC:

2866

AN:

5142

South Asian (SAS)

AF:

0.720

AC:

3464

AN:

4812

European-Finnish (FIN)

AF:

0.850

AC:

9000

AN:

10588

Middle Eastern (MID)

AF:

0.733

AC:

214

AN:

292

European-Non Finnish (NFE)

AF:

0.750

AC:

50947

AN:

67966

Other (OTH)

AF:

0.702

AC:

1482

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1480

2960

4441

5921

7401

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

852

1704

2556

3408

4260

<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:

0.740

Hom.:

105915

Bravo

AF:

0.738

Asia WGS

AF:

0.639

AC:

2225

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.89

CADD

Benign

3.5

(source)

DANN

Benign

0.44

PhyloP100

-0.11

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over