3-171071330-T-C

Variant names:

• chr3-171071330-T-C
• rs192304760
• NM_015028.4:c.3449-7A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_015028.4(TNIK):​c.3449-7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000712 in 1,403,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: TNIK NM_015028.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002557
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.728
• 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):

• 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

ENSG00000286856 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	NM_015028.4	MANE Select	c.3449-7A>G		splice_region intron	N/A	NP_055843.1	Q9UKE5-1
	TNIK	NM_001161560.3		c.3425-7A>G		splice_region intron	N/A	NP_001155032.1	Q9UKE5-4
	TNIK	NM_001161561.3		c.3362-7A>G		splice_region intron	N/A	NP_001155033.1	Q9UKE5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	ENST00000436636.7	TSL:1 MANE Select	c.3449-7A>G		splice_region intron	N/A	ENSP00000399511.2	Q9UKE5-1
	TNIK	ENST00000284483.12	TSL:1	c.3425-7A>G		splice_region intron	N/A	ENSP00000284483.8	Q9UKE5-4
	TNIK	ENST00000357327.9	TSL:1	c.3362-7A>G		splice_region intron	N/A	ENSP00000349880.5	Q9UKE5-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000544 AC: 1 AN: 183662 AF XY: 0.0000102

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.12e-7 AC: 1 AN: 1403700 Hom.: 0 Cov.: 26 AF XY: 0.00000144 AC XY: 1 AN XY: 695228

African (AFR) AF: 0.00 AC: 0 AN: 32270

American (AMR) AF: 0.00 AC: 0 AN: 37736

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25166

East Asian (EAS) AF: 0.00 AC: 0 AN: 38430

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78288

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48170

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1079676

Other (OTH) AF: 0.00 AC: 0 AN: 58320

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	7.2
DANN	Benign	0.82
PhyloP100		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00026
dbscSNV1_RF	Benign	0.0060
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: rs192304760; hg19: chr3-170789119;