chr15-88256014-C-T

Variant names:

• chr15-88256014-C-T
• rs373123404
• NM_001012338.3:c.140G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001012338.3(NTRK3):​c.140G>A​(p.Arg47Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000115 in 1,613,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000086 (0 hom., cov: 30)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: NTRK3 NM_001012338.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.124411136).
• BS2: High AC in GnomAd4 at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK3	NM_001012338.3	c.140G>A	p.Arg47Gln	missense_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.140G>A	p.Arg47Gln	missense_variant	Exon 3 of 20	1	NM_001012338.3	ENSP00000485864.1

Frequencies

GnomAD3 genomes AF: 0.0000857 AC: 13 AN: 151754 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000480

GnomAD3 exomes AF: 0.0000676 AC: 17 AN: 251296 Hom.: 0 AF XY: 0.0000515 AC XY: 7 AN XY: 135890

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000118 AC: 172 AN: 1461700 Hom.: 0 Cov.: 33 AF XY: 0.000118 AC XY: 86 AN XY: 727164

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000148

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000857 AC: 13 AN: 151754 Hom.: 0 Cov.: 30 AF XY: 0.0000405 AC XY: 3 AN XY: 74114

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000480

Alfa AF: 0.000212 Hom.: 0

Bravo AF: 0.000106

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 25, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.140G>A (p.R47Q) alteration is located in exon 3 (coding exon 1) of the NTRK3 gene. This alteration results from a G to A substitution at nucleotide position 140, causing the arginine (R) at amino acid position 47 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.12
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	.;D;.;D;.;T;.;.;.;.
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.96	D;.;D;D;D;D;.;D;.;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.077	D
MutationAssessor	Benign	0.0	N;N;N;N;N;.;N;.;N;N
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.050	N;.;N;N;N;.;N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.43	T;.;T;T;T;.;T;T;T;T
Sift4G	Benign	0.49	T;T;T;T;T;T;T;T;T;T
Polyphen		0.0010	B;B;.;B;.;.;.;.;.;.
Vest4		0.29
MVP		0.59
MPC		0.53
ClinPred		0.056	T
GERP RS		2.6
Varity_R		0.072
gMVP		0.46

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: rs373123404; hg19: chr15-88799245;