chr17-7383857-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_003985.6(TNK1):ā€‹c.575T>Cā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

TNK1
NM_003985.6 missense

Scores

3
9
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.88
Variant links:
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]

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ACMG classification

Classification made for transcript

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
TNK1NM_003985.6 linkc.575T>C p.Leu192Pro missense_variant Exon 5 of 13 ENST00000688331.1 NP_003976.2 Q13470-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TNK1ENST00000688331.1 linkc.575T>C p.Leu192Pro missense_variant Exon 5 of 13 NM_003985.6 ENSP00000509611.1 Q13470-2
TNK1ENST00000576812.5 linkc.575T>C p.Leu192Pro missense_variant Exon 5 of 13 1 ENSP00000459799.1 Q13470-1
TNK1ENST00000570896.5 linkc.575T>C p.Leu192Pro missense_variant Exon 6 of 14 5 ENSP00000458834.1 Q13470-2

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
show subpopulations
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
LINK: link

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; API