chr17-7384062-C-A

Position:

• chr17-7384062-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_003985.6(TNK1):​c.675C>A​(p.Phe225Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000217 in 1,383,590 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: TNK1 NM_003985.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.847

Genes affected

TNK1 (HGNC:11940): (tyrosine kinase non receptor 1) The protein encoded by this gene belongs to the tyrosine protein kinase family. Tyrosine protein kinases are important regulators of intracellular signal transduction pathways, mediating cellular proliferation, survival, and development. This gene is highly expressed in fetal tissues and at lower levels in few adult tissues, thus may function in signaling pathways utilized broadly during fetal development, and more selectively in adult tissues. It plays a negative regulatory role in the Ras-Raf1-MAPK pathway, and knockout mice have been shown to develop spontaneous tumors, suggesting a role as a tumor suppressor gene. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TNK1	NM_003985.6	c.675C>A	p.Phe225Leu	missense_variant	6/13	ENST00000688331.1	NP_003976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TNK1	ENST00000688331.1	c.675C>A	p.Phe225Leu	missense_variant	6/13		NM_003985.6	ENSP00000509611.1
TNK1	ENST00000576812.5	c.675C>A	p.Phe225Leu	missense_variant	6/13	1		ENSP00000459799.1
TNK1	ENST00000570896.5	c.675C>A	p.Phe225Leu	missense_variant	7/14	5		ENSP00000458834.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000217 AC: 3 AN: 1383590 Hom.: 0 Cov.: 34 AF XY: 0.00000146 AC XY: 1 AN XY: 683254

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 22, 2022

The c.675C>A (p.F225L) alteration is located in exon 6 (coding exon 5) of the TNK1 gene. This alteration results from a C to A substitution at nucleotide position 675, causing the phenylalanine (F) at amino acid position 225 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.0049	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.55	.;D
Eigen	Benign	0.14
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.92	D
M_CAP	Benign	0.070	D
MetaRNN	Uncertain	0.58	D;D
MetaSVM	Benign	-0.78	T
MutationAssessor	Benign	0.30	N;N
MutationTaster	Benign	0.96	D;D;D
PrimateAI	Pathogenic	0.89	D
Sift4G	Uncertain	0.020	D;D
Polyphen		0.99	D;D
Vest4		0.54
MutPred		0.73		Loss of catalytic residue at F225 (P = 0.107);Loss of catalytic residue at F225 (P = 0.107);
MVP		0.52
MPC		0.49
ClinPred		0.90	D
GERP RS		0.85
Varity_R		0.15
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs1480371312; hg19: chr17-7287381;