15-87933149-A-C

Variant names:

• chr15-87933149-A-C
• rs748800325
• NM_001012338.3:c.1752T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001012338.3(NTRK3):​c.1752T>G​(p.Asp584Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D584D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.402
• Publications: 1 publications found

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]

NTRK3 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.768

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.1752T>G	p.Asp584Glu	missense_variant	Exon 16 of 20	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.1752T>G	p.Asp584Glu	missense_variant	Exon 16 of 20	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.80	.;D;.;D;.;T;.;.;.
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.25	N
LIST_S2	Uncertain	0.97	D;.;D;D;D;D;.;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.77	D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationAssessor	Benign	0.41	N;N;.;N;.;.;.;.;.
PhyloP100		-0.40
PrimateAI	Pathogenic	0.86	D
PROVEAN	Uncertain	-3.3	D;.;N;D;D;.;D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;.;T;D;D;.;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;D;.;.;.;D;.
Vest4		0.74
MutPred		0.78		Gain of disorder (P = 0.086);Gain of disorder (P = 0.086);.;Gain of disorder (P = 0.086);.;Gain of disorder (P = 0.086);.;.;.;
MVP		0.85
MPC		1.2
ClinPred		0.99	D
GERP RS		-5.0
PromoterAI		0.0066	Neutral
Varity_R		0.88
gMVP		0.57
Mutation Taster		=26/74	disease causing

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: rs748800325; hg19: chr15-88476380;