NM_015028.4:c.3449-7A>T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_015028.4(TNIK):​c.3449-7A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,555,952 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0041 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0060 (49 hom.)
• Consequence: TNIK NM_015028.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002403
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 3-171071330-T-A is Benign according to our data. Variant chr3-171071330-T-A is described in ClinVar as Benign. ClinVar VariationId is 769283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNIK	NM_015028.4	MANE Select	c.3449-7A>T		splice_region intron	N/A	NP_055843.1	Q9UKE5-1
	TNIK	NM_001161560.3		c.3425-7A>T		splice_region intron	N/A	NP_001155032.1	Q9UKE5-4
	TNIK	NM_001161561.3		c.3362-7A>T		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>T		splice_region intron	N/A	ENSP00000399511.2	Q9UKE5-1
	TNIK	ENST00000284483.12	TSL:1	c.3425-7A>T		splice_region intron	N/A	ENSP00000284483.8	Q9UKE5-4
	TNIK	ENST00000357327.9	TSL:1	c.3362-7A>T		splice_region intron	N/A	ENSP00000349880.5	Q9UKE5-2

Frequencies

GnomAD3 genomes AF: 0.00409 AC: 622 AN: 152176 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0108

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00565

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.00507 AC: 932 AN: 183662 AF XY: 0.00577

Gnomad AFR exome AF: 0.000923

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00113

Gnomad EAS exome AF: 0.0000715

Gnomad FIN exome AF: 0.000552

Gnomad NFE exome AF: 0.00600

Gnomad OTH exome AF: 0.00702

GnomAD4 exome AF: 0.00604 AC: 8484 AN: 1403658 Hom.: 49 Cov.: 26 AF XY: 0.00633 AC XY: 4398 AN XY: 695204

African (AFR) AF: 0.000899 AC: 29 AN: 32270

American (AMR) AF: 0.00395 AC: 149 AN: 37732

Ashkenazi Jewish (ASJ) AF: 0.000755 AC: 19 AN: 25166

East Asian (EAS) AF: 0.0000520 AC: 2 AN: 38430

South Asian (SAS) AF: 0.0140 AC: 1097 AN: 78280

European-Finnish (FIN) AF: 0.000664 AC: 32 AN: 48170

Middle Eastern (MID) AF: 0.0108 AC: 61 AN: 5644

European-Non Finnish (NFE) AF: 0.00622 AC: 6718 AN: 1079656

Other (OTH) AF: 0.00647 AC: 377 AN: 58310

GnomAD4 genome AF: 0.00408 AC: 621 AN: 152294 Hom.: 3 Cov.: 32 AF XY: 0.00363 AC XY: 270 AN XY: 74466

African (AFR) AF: 0.00120 AC: 50 AN: 41586

American (AMR) AF: 0.00660 AC: 101 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0106 AC: 51 AN: 4822

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10612

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

European-Non Finnish (NFE) AF: 0.00565 AC: 384 AN: 68000

Other (OTH) AF: 0.00568 AC: 12 AN: 2114

Alfa AF: 0.00484 Hom.: 0

Bravo AF: 0.00479

Asia WGS AF: 0.00434 AC: 15 AN: 3474

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.44
CADD	Benign	6.2
DANN	Benign	0.81
PhyloP100		0.73
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
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;