rs6496469

Variant names:

• chr15-88192079-A-G
• rs6496469
• NM_001012338.3:c.249-7780T>C

Variant summary

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

The NM_001012338.3(NTRK3):​c.249-7780T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.257 in 152,218 control chromosomes in the GnomAD database, including 5,636 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 0.26 (5636 hom., cov: 33)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.60
• Publications: 8 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.249-7780T>C		intron_variant	Intron 3 of 19	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.249-7780T>C		intron_variant	Intron 3 of 19	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.257 AC: 39014 AN: 152100 Hom.: 5614 Cov.: 33

Gnomad AFR AF: 0.378

Gnomad AMI AF: 0.206

Gnomad AMR AF: 0.250

Gnomad ASJ AF: 0.191

Gnomad EAS AF: 0.144

Gnomad SAS AF: 0.320

Gnomad FIN AF: 0.129

Gnomad MID AF: 0.294

Gnomad NFE AF: 0.213

Gnomad OTH AF: 0.227

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

GnomAD4 genome AF: 0.257 AC: 39082 AN: 152218 Hom.: 5636 Cov.: 33 AF XY: 0.252 AC XY: 18765 AN XY: 74420

African (AFR) AF: 0.378 AC: 15695 AN: 41518

American (AMR) AF: 0.250 AC: 3820 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 662 AN: 3470

East Asian (EAS) AF: 0.145 AC: 748 AN: 5176

South Asian (SAS) AF: 0.319 AC: 1542 AN: 4828

European-Finnish (FIN) AF: 0.129 AC: 1370 AN: 10612

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.213 AC: 14485 AN: 67996

Other (OTH) AF: 0.229 AC: 484 AN: 2112

Alfa AF: 0.225 Hom.: 12799

Bravo AF: 0.267

Asia WGS AF: 0.268 AC: 932 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.0010
DANN	Benign	0.59
PhyloP100		-4.6
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: rs6496469; hg19: chr15-88735310;