rs2009966

Variant names:

• chr15-87997493-G-A
• rs2009966
• NM_001012338.3:c.1585+35364C>T

Variant summary

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

The NM_001012338.3(NTRK3):​c.1585+35364C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 151,760 control chromosomes in the GnomAD database, including 17,768 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 0.47 (17768 hom., cov: 31)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.979
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.661 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001012338.3. 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
	NTRK3	NM_001012338.3	MANE Select	c.1585+35364C>T		intron	N/A	NP_001012338.1	X5D2R1
	NTRK3	NM_001375810.1		c.1585+35364C>T		intron	N/A	NP_001362739.1	Q16288-1
	NTRK3	NM_001375811.1		c.1585+35364C>T		intron	N/A	NP_001362740.1	X5D7M5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NTRK3	ENST00000629765.3	TSL:1 MANE Select	c.1585+35364C>T		intron	N/A	ENSP00000485864.1	Q16288-1
	NTRK3	ENST00000557856.5	TSL:1	c.1561+35364C>T		intron	N/A	ENSP00000453959.1	Q16288-5
	NTRK3	ENST00000558676.5	TSL:1	c.1561+35364C>T		intron	N/A	ENSP00000453511.1	H0YM90

Frequencies

GnomAD3 genomes AF: 0.466 AC: 70614 AN: 151642 Hom.: 17729 Cov.: 31

Gnomad AFR AF: 0.667

Gnomad AMI AF: 0.253

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.407

Gnomad OTH AF: 0.440

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

GnomAD4 genome AF: 0.466 AC: 70700 AN: 151760 Hom.: 17768 Cov.: 31 AF XY: 0.459 AC XY: 34055 AN XY: 74164

African (AFR) AF: 0.668 AC: 27604 AN: 41344

American (AMR) AF: 0.408 AC: 6219 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1478 AN: 3466

East Asian (EAS) AF: 0.207 AC: 1069 AN: 5156

South Asian (SAS) AF: 0.458 AC: 2195 AN: 4794

European-Finnish (FIN) AF: 0.302 AC: 3174 AN: 10522

Middle Eastern (MID) AF: 0.503 AC: 148 AN: 294

European-Non Finnish (NFE) AF: 0.407 AC: 27654 AN: 67930

Other (OTH) AF: 0.441 AC: 929 AN: 2106

Alfa AF: 0.429 Hom.: 7963

Bravo AF: 0.479

Asia WGS AF: 0.378 AC: 1314 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.10
DANN	Benign	0.82
PhyloP100		-0.98
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: rs2009966; hg19: chr15-88540724;