15-87933033-C-T

Variant summary

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

The NM_001012338.3(NTRK3):c.1868G>A(p.Gly623Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as other (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G623A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 7.71

Genes affected

NTRK3 (HGNC:8033): (neurotrophic receptor tyrosine kinase 3) This gene encodes a member of the neurotrophic tyrosine receptor kinase (NTRK) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. Signalling through this kinase leads to cell differentiation and may play a role in the development of proprioceptive neurons that sense body position. Mutations in this gene have been associated with medulloblastomas, secretory breast carcinomas and other cancers. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 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, 0.976

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK3	NM_001012338.3	c.1868G>A	p.Gly623Glu	missense_variant	16/20	ENST00000629765.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK3	ENST00000629765.3	c.1868G>A	p.Gly623Glu	missense_variant	16/20	1	NM_001012338.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Cabozantinib resistance;na:Entrectinib resistance;na:Larotrectinib resistance;na:Repotrectinib resistance;na:Selitrectinib resistance Other:1

other, no assertion criteria provided

research

Davare Laboratory, Oregon Health & Science University

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Kinase domain mutation within ETV6-NTRK3 fusion imposes resistance to multiple NTRK kinase inhibitors; Induces drug resistance when present in context of ETV6-NTRK3 fusion protein; Patient tumor harboring this mutation progressed on NTRK targeted therapy. In cell based assays, ETV6-NTRK3 with NTRK3 G623E mutation conferred high level of resistance to multiple NTRK tyrosine kinase inhibitors. Likely unresponsive to NTRK inhibitors

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
Cadd	Pathogenic	29
Dann	Uncertain	1.0
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;.;D;D;D;D;.;D;D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.0	M;M;.;M;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-6.9	D;.;.;D;D;.;D;D;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.;.;D;D;.;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;.;D;.
Vest4		0.95
MutPred		0.91		Loss of catalytic residue at G623 (P = 0.0152);Loss of catalytic residue at G623 (P = 0.0152);.;Loss of catalytic residue at G623 (P = 0.0152);.;Loss of catalytic residue at G623 (P = 0.0152);.;.;.;
MVP		0.92
MPC		1.5
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.98
gMVP		0.92

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: chr15-88476264; COSMIC: COSV62295522;