NM_015028.4:c.124-18A>G

Variant names:

• chr3-171228239-T-C
• rs76246285
• NM_015028.4:c.124-18A>G

Variant summary

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

The NM_015028.4(TNIK):​c.124-18A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,234 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (5 hom.)
• Consequence: TNIK NM_015028.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.01
• 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=-0.83).
• BP6: Variant 3-171228239-T-C is Benign according to our data. Variant chr3-171228239-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 446077.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00643 (978/152214) while in subpopulation AFR AF = 0.0221 (917/41536). AF 95% confidence interval is 0.0209. There are 10 homozygotes in GnomAd4. There are 457 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AR,Unknown gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	NM_015028.4	MANE Select	c.124-18A>G		intron	N/A	NP_055843.1
	TNIK	NM_001161560.3		c.124-18A>G		intron	N/A	NP_001155032.1
	TNIK	NM_001161561.3		c.124-18A>G		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.124-18A>G		intron	N/A	ENSP00000399511.2
	TNIK	ENST00000284483.12	TSL:1	c.124-18A>G		intron	N/A	ENSP00000284483.8
	TNIK	ENST00000357327.9	TSL:1	c.124-18A>G		intron	N/A	ENSP00000349880.5

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152096 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00249

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: 0.000132

Gnomad OTH AF: 0.00624

GnomAD2 exomes AF: 0.00166 AC: 414 AN: 248654 AF XY: 0.00120

Gnomad AFR exome AF: 0.0238

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000571 AC: 834 AN: 1461020 Hom.: 5 Cov.: 30 AF XY: 0.000477 AC XY: 347 AN XY: 726788

African (AFR) AF: 0.0202 AC: 675 AN: 33432

American (AMR) AF: 0.000963 AC: 43 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86242

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

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000153 AC: 17 AN: 1111420

Other (OTH) AF: 0.00159 AC: 96 AN: 60324

GnomAD4 genome AF: 0.00643 AC: 978 AN: 152214 Hom.: 10 Cov.: 32 AF XY: 0.00614 AC XY: 457 AN XY: 74416

African (AFR) AF: 0.0221 AC: 917 AN: 41536

American (AMR) AF: 0.00249 AC: 38 AN: 15272

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: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68008

Other (OTH) AF: 0.00618 AC: 13 AN: 2104

Alfa AF: 0.00300 Hom.: 0

Bravo AF: 0.00738

Asia WGS AF: 0.00144 AC: 5 AN: 3478

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	-0.83
CADD	Benign	0.077
DANN	Benign	0.36
PhyloP100		-1.0
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: rs76246285; hg19: chr3-170946028;