NM_003985.6:c.575T>C

Variant names:

• chr17-7383857-T-C
• NM_003985.6:c.575T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_003985.6(TNK1):​c.575T>C​(p.Leu192Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,456,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: TNK1 NM_003985.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.88

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TNK1	NM_003985.6	c.575T>C	p.Leu192Pro	missense_variant	Exon 5 of 13	ENST00000688331.1	NP_003976.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TNK1	ENST00000688331.1	c.575T>C	p.Leu192Pro	missense_variant	Exon 5 of 13		NM_003985.6	ENSP00000509611.1
TNK1	ENST00000576812.5	c.575T>C	p.Leu192Pro	missense_variant	Exon 5 of 13	1		ENSP00000459799.1
TNK1	ENST00000570896.5	c.575T>C	p.Leu192Pro	missense_variant	Exon 6 of 14	5		ENSP00000458834.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1456686 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 724148

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000227

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.575T>C (p.L192P) alteration is located in exon 5 (coding exon 4) of the TNK1 gene. This alteration results from a T to C substitution at nucleotide position 575, causing the leucine (L) at amino acid position 192 to be replaced by a proline (P). 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	0.59
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.58	.;D
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.5	L;L
PrimateAI	Uncertain	0.70	T
Sift4G	Uncertain	0.0050	D;D
Polyphen		1.0	D;D
Vest4		0.88
MutPred		0.83		Gain of disorder (P = 0.0129);Gain of disorder (P = 0.0129);
MVP		0.90
MPC		0.93
ClinPred		0.95	D
GERP RS		2.8
Varity_R		0.35
gMVP		0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7287176;