15-88020640-G-C

Variant names:

• chr15-88020640-G-C
• rs999905
• NM_001012338.3:c.1585+12217C>G

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+12217C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.307 in 151,948 control chromosomes in the GnomAD database, including 7,334 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 0.31 (7334 hom., cov: 32)
• Consequence: NTRK3 NM_001012338.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.696
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.382 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.1585+12217C>G		intron_variant	Intron 14 of 19	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.1585+12217C>G		intron_variant	Intron 14 of 19	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46586 AN: 151832 Hom.: 7327 Cov.: 32

Gnomad AFR AF: 0.289

Gnomad AMI AF: 0.240

Gnomad AMR AF: 0.309

Gnomad ASJ AF: 0.389

Gnomad EAS AF: 0.204

Gnomad SAS AF: 0.396

Gnomad FIN AF: 0.244

Gnomad MID AF: 0.408

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.317

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

GnomAD4 genome AF: 0.307 AC: 46618 AN: 151948 Hom.: 7334 Cov.: 32 AF XY: 0.305 AC XY: 22689 AN XY: 74274

African (AFR) AF: 0.289 AC: 11989 AN: 41424

American (AMR) AF: 0.308 AC: 4708 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.389 AC: 1348 AN: 3466

East Asian (EAS) AF: 0.203 AC: 1048 AN: 5156

South Asian (SAS) AF: 0.397 AC: 1910 AN: 4816

European-Finnish (FIN) AF: 0.244 AC: 2573 AN: 10540

Middle Eastern (MID) AF: 0.390 AC: 114 AN: 292

European-Non Finnish (NFE) AF: 0.324 AC: 22042 AN: 67946

Other (OTH) AF: 0.316 AC: 668 AN: 2116

Alfa AF: 0.178 Hom.: 371

Bravo AF: 0.306

Asia WGS AF: 0.309 AC: 1071 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.077
DANN	Benign	0.38
PhyloP100		-0.70
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: rs999905; hg19: chr15-88563871; COSMIC: COSV58122395;