rs3784406

Variant names:

• chr15-88142099-C-T
• rs3784406
• NM_001012338.3:c.465-4538G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001012338.3(NTRK3):​c.465-4538G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.513 in 152,082 control chromosomes in the GnomAD database, including 21,760 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.51 (21760 hom., cov: 33)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.365
• Publications: 6 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: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.747 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.465-4538G>A		intron_variant	Intron 6 of 19	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.465-4538G>A		intron_variant	Intron 6 of 19	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.513 AC: 77907 AN: 151964 Hom.: 21708 Cov.: 33

Gnomad AFR AF: 0.754

Gnomad AMI AF: 0.359

Gnomad AMR AF: 0.406

Gnomad ASJ AF: 0.507

Gnomad EAS AF: 0.368

Gnomad SAS AF: 0.446

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.525

Gnomad NFE AF: 0.431

Gnomad OTH AF: 0.473

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.513 AC: 78018 AN: 152082 Hom.: 21760 Cov.: 33 AF XY: 0.506 AC XY: 37648 AN XY: 74338

African (AFR) AF: 0.754 AC: 31283 AN: 41492

American (AMR) AF: 0.405 AC: 6202 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.507 AC: 1761 AN: 3470

East Asian (EAS) AF: 0.368 AC: 1898 AN: 5154

South Asian (SAS) AF: 0.447 AC: 2151 AN: 4812

European-Finnish (FIN) AF: 0.372 AC: 3927 AN: 10560

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.431 AC: 29303 AN: 67984

Other (OTH) AF: 0.477 AC: 1008 AN: 2112

Alfa AF: 0.514 Hom.: 4383

Bravo AF: 0.523

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	5.3
DANN	Benign	0.57
PhyloP100		-0.36
Mutation Taster		=100/0	polymorphism (auto)

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: rs3784406; hg19: chr15-88685330; COSMIC: COSV58133554; COSMIC: COSV58133554;