15-87933134-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BA1

The NM_001012338.3(NTRK3):c.1767C>T(p.Ala589=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00468 in 1,614,048 control chromosomes in the GnomAD database, including 462 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0057 (55 hom., cov: 32)
  • Exomes 𝑓: 0.0046 (407 hom.)
• Consequence: NTRK3 NM_001012338.3 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -5.29

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 15-87933134-G-A is Benign according to our data. Variant chr15-87933134-G-A is described in ClinVar as [Benign]. Clinvar id is 3059099.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-5.29 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK3	NM_001012338.3	c.1767C>T	p.Ala589=	synonymous_variant	16/20	ENST00000629765.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK3	ENST00000629765.3	c.1767C>T	p.Ala589=	synonymous_variant	16/20	1	NM_001012338.3

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 862 AN: 152058 Hom.: 55 Cov.: 32

Gnomad AFR AF: 0.000556

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.141

Gnomad SAS AF: 0.00768

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.00955

GnomAD3 exomes AF: 0.0122 AC: 3062 AN: 251206 Hom.: 202 AF XY: 0.0112 AC XY: 1526 AN XY: 135752

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.152

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.000528

Gnomad OTH exome AF: 0.00735

GnomAD4 exome AF: 0.00458 AC: 6695 AN: 1461872 Hom.: 407 Cov.: 31 AF XY: 0.00446 AC XY: 3245 AN XY: 727236

Gnomad4 AFR exome AF: 0.000239

Gnomad4 AMR exome AF: 0.00157

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.00286

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000333

Gnomad4 OTH exome AF: 0.00896

GnomAD4 genome AF: 0.00565 AC: 860 AN: 152176 Hom.: 55 Cov.: 32 AF XY: 0.00587 AC XY: 437 AN XY: 74404

Gnomad4 AFR AF: 0.000554

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.141

Gnomad4 SAS AF: 0.00789

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.000397

Gnomad4 OTH AF: 0.00945

Alfa AF: 0.00108 Hom.: 7

Bravo AF: 0.00631

Asia WGS AF: 0.0510 AC: 178 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.000593

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

NTRK3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 03, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	0.28
Dann	Benign	0.61

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

Publications

LitVar

Other links and lift over

dbSNP: rs2277580; hg19: chr15-88476365; COSMIC: COSV62314881; COSMIC: COSV62314881;