15-88256154-C-T

Variant names:

• chr15-88256154-C-T
• rs140166305
• NM_001012338.3:c.-1G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Moderate BP6 BS2

The NM_001012338.3(NTRK3):​c.-1G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00159 in 1,598,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0010 (1 hom., cov: 28)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: NTRK3 NM_001012338.3 5_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.18

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-AS1 (HGNC:27532): (NTRK3 antisense RNA 1)

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 15-88256154-C-T is Benign according to our data. Variant chr15-88256154-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3041033.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS2: High AC in GnomAd4 at 153 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.-1G>A		5_prime_UTR_variant	Exon 3 of 20	ENST00000629765.3	NP_001012338.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK3	ENST00000629765.3	c.-1G>A		5_prime_UTR_variant	Exon 3 of 20	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.00104 AC: 153 AN: 147628 Hom.: 1 Cov.: 28

Gnomad AFR AF: 0.000351

Gnomad AMI AF: 0.0123

Gnomad AMR AF: 0.000135

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000439

Gnomad FIN AF: 0.00143

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00164

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00109 AC: 264 AN: 243086 Hom.: 1 AF XY: 0.00101 AC XY: 134 AN XY: 132040

Gnomad AFR exome AF: 0.000375

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000229

Gnomad FIN exome AF: 0.00184

Gnomad NFE exome AF: 0.00183

Gnomad OTH exome AF: 0.00116

GnomAD4 exome AF: 0.00165 AC: 2390 AN: 1451202 Hom.: 2 Cov.: 33 AF XY: 0.00160 AC XY: 1157 AN XY: 721960

Gnomad4 AFR exome AF: 0.000180

Gnomad4 AMR exome AF: 0.000337

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.00167

Gnomad4 NFE exome AF: 0.00199

Gnomad4 OTH exome AF: 0.00100

GnomAD4 genome AF: 0.00104 AC: 153 AN: 147730 Hom.: 1 Cov.: 28 AF XY: 0.000946 AC XY: 68 AN XY: 71898

Gnomad4 AFR AF: 0.000350

Gnomad4 AMR AF: 0.000135

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000440

Gnomad4 FIN AF: 0.00143

Gnomad4 NFE AF: 0.00164

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00128 Hom.: 0

Bravo AF: 0.00109

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

NTRK3-related disorder Benign:1

Mar 06, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely 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	-0.43
CADD	Benign	20
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs140166305; hg19: chr15-88799385; COSMIC: COSV100446016; COSMIC: COSV100446016;