3-171194514-T-G

Variant names:

• chr3-171194514-T-G
• rs141160238
• NM_015028.4:c.417+11A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000436636.7(TNIK):​c.417+11A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,612,900 control chromosomes in the GnomAD database, including 44 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.010 (28 hom., cov: 32)
  • Exomes 𝑓: 0.00095 (16 hom.)
• Consequence: TNIK ENST00000436636.7 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.597
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-171194514-T-G is Benign according to our data. Variant chr3-171194514-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 445516.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0101 (1535/152316) while in subpopulation AFR AF = 0.0353 (1466/41566). AF 95% confidence interval is 0.0338. There are 28 homozygotes in GnomAd4. There are 710 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 28 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000436636.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	NM_015028.4	MANE Select	c.417+11A>C		intron	N/A	NP_055843.1
	TNIK	NM_001161560.3		c.417+11A>C		intron	N/A	NP_001155032.1
	TNIK	NM_001161561.3		c.417+11A>C		intron	N/A	NP_001155033.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	ENST00000436636.7	TSL:1 MANE Select	c.417+11A>C		intron	N/A	ENSP00000399511.2
	TNIK	ENST00000284483.12	TSL:1	c.417+11A>C		intron	N/A	ENSP00000284483.8
	TNIK	ENST00000357327.9	TSL:1	c.417+11A>C		intron	N/A	ENSP00000349880.5

Frequencies

GnomAD3 genomes AF: 0.0101 AC: 1533 AN: 152198 Hom.: 28 Cov.: 32

Gnomad AFR AF: 0.0353

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00261 AC: 649 AN: 248516 AF XY: 0.00192

Gnomad AFR exome AF: 0.0378

Gnomad AMR exome AF: 0.00154

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000532

Gnomad OTH exome AF: 0.000664

GnomAD4 exome AF: 0.000948 AC: 1385 AN: 1460584 Hom.: 16 Cov.: 30 AF XY: 0.000797 AC XY: 579 AN XY: 726624

African (AFR) AF: 0.0339 AC: 1133 AN: 33448

American (AMR) AF: 0.00141 AC: 63 AN: 44588

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26112

East Asian (EAS) AF: 0.00 AC: 0 AN: 39666

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111184

Other (OTH) AF: 0.00250 AC: 151 AN: 60320

GnomAD4 genome AF: 0.0101 AC: 1535 AN: 152316 Hom.: 28 Cov.: 32 AF XY: 0.00953 AC XY: 710 AN XY: 74488

African (AFR) AF: 0.0353 AC: 1466 AN: 41566

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68018

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00293 Hom.: 2

Bravo AF: 0.0114

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.2
DANN	Benign	0.55
PhyloP100		0.60
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs141160238; hg19: chr3-170912303;