17-7383853-C-A

Variant names:

• chr17-7383853-C-A
• rs1371921316
• NM_003985.6:c.571C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003985.6(TNK1):​c.571C>A​(p.Pro191Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,457,902 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P191A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: TNK1 NM_003985.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.72
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.879

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003985.6. 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
	TNK1	NM_003985.6	MANE Select	c.571C>A	p.Pro191Thr	missense	Exon 5 of 13	NP_003976.2	Q13470-2
	TNK1	NM_001251902.3		c.571C>A	p.Pro191Thr	missense	Exon 5 of 13	NP_001238831.1	Q13470-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TNK1	ENST00000688331.1	MANE Select	c.571C>A	p.Pro191Thr	missense	Exon 5 of 13	ENSP00000509611.1	Q13470-2
	TNK1	ENST00000576812.5	TSL:1	c.571C>A	p.Pro191Thr	missense	Exon 5 of 13	ENSP00000459799.1	Q13470-1
	TNK1	ENST00000570896.5	TSL:5	c.571C>A	p.Pro191Thr	missense	Exon 6 of 14	ENSP00000458834.1	Q13470-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000416 AC: 1 AN: 240238 AF XY: 0.00000765

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000296

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: 0.00000274 AC: 4 AN: 1457902 Hom.: 1 Cov.: 34 AF XY: 0.00000276 AC XY: 2 AN XY: 724912

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33402

American (AMR) AF: 0.0000904 AC: 4 AN: 44250

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.00 AC: 0 AN: 39536

South Asian (SAS) AF: 0.00 AC: 0 AN: 85520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52816

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110440

Other (OTH) AF: 0.00 AC: 0 AN: 60144

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	0.0018	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.65	D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.065	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Benign	1.3	L
PhyloP100		5.7
PrimateAI	Uncertain	0.76	T
Sift4G	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.82
MutPred		0.76		Gain of catalytic residue at P191 (P = 0.0483)
MVP		0.83
MPC		0.77
ClinPred		0.92	D
GERP RS		3.9
Varity_R		0.29
gMVP		0.43

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

Other links and lift over

dbSNP: rs1371921316; hg19: chr17-7287172;