15-88256006-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001012338.3(NTRK3):​c.148G>A​(p.Asp50Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,488 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D50Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NTRK3
NM_001012338.3 missense

Scores

1
5
13

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.60
Variant links:
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)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.12880254).
BS2
High AC in GnomAdExome4 at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK3NM_001012338.3 linkc.148G>A p.Asp50Asn missense_variant Exon 3 of 20 ENST00000629765.3 NP_001012338.1 Q16288-1X5D2R1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NTRK3ENST00000629765.3 linkc.148G>A p.Asp50Asn missense_variant Exon 3 of 20 1 NM_001012338.3 ENSP00000485864.1 Q16288-1

Frequencies

GnomAD3 genomes
AF:
0.00000659
AC:
1
AN:
151826
Hom.:
0
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000194
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000547
AC:
8
AN:
1461662
Hom.:
0
Cov.:
33
AF XY:
0.00000550
AC XY:
4
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000659
AC:
1
AN:
151826
Hom.:
0
Cov.:
30
AF XY:
0.0000135
AC XY:
1
AN XY:
74140
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000194
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 15, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.148G>A (p.D50N) 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 148, causing the aspartic acid (D) at amino acid position 50 to be replaced by an asparagine (N). 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
0.11
BayesDel_addAF
Benign
-0.015
T
BayesDel_noAF
Benign
-0.26
CADD
Benign
20
DANN
Benign
0.97
DEOGEN2
Uncertain
0.52
.;D;.;D;.;T;.;.;.;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.31
FATHMM_MKL
Benign
0.46
N
LIST_S2
Uncertain
0.88
D;.;D;D;D;D;.;D;.;D
M_CAP
Uncertain
0.28
D
MetaRNN
Benign
0.13
T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.083
D
MutationAssessor
Benign
0.20
N;N;N;N;N;.;N;.;N;N
PrimateAI
Pathogenic
0.89
D
PROVEAN
Benign
-0.17
N;.;N;N;N;.;N;N;N;N
REVEL
Uncertain
0.31
Sift
Benign
0.42
T;.;T;T;T;.;T;T;T;T
Sift4G
Benign
0.52
T;T;T;T;T;T;T;T;T;T
Polyphen
0.0040
B;B;.;B;.;.;.;.;.;.
Vest4
0.12
MutPred
0.44
Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);Loss of disorder (P = 0.2514);
MVP
0.44
MPC
0.44
ClinPred
0.41
T
GERP RS
2.9
Varity_R
0.10
gMVP
0.48

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs907290552; hg19: chr15-88799237; API