15-88256113-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001012338.3(NTRK3):​c.41G>C​(p.Arg14Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,460,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14Q) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 29)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

NTRK3
NM_001012338.3 missense

Scores

3
9
7

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.31
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)

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.773

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK3NM_001012338.3 linkc.41G>C p.Arg14Pro 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.41G>C p.Arg14Pro missense_variant Exon 3 of 20 1 NM_001012338.3 ENSP00000485864.1 Q16288-1

Frequencies

GnomAD3 genomes
Cov.:
29
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1460966
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726824
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
Cov.:
29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Pathogenic
0.22
D
BayesDel_noAF
Uncertain
0.070
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.40
.;T;.;T;.;T;.;.;.;.
Eigen
Uncertain
0.32
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.91
D;.;D;D;D;D;.;D;.;D
M_CAP
Uncertain
0.25
D
MetaRNN
Pathogenic
0.77
D;D;D;D;D;D;D;D;D;D
MetaSVM
Benign
-0.35
T
MutationAssessor
Benign
0.90
L;L;L;L;L;.;L;.;L;L
PrimateAI
Pathogenic
0.86
D
PROVEAN
Benign
-0.81
N;.;N;N;N;.;N;N;N;N
REVEL
Uncertain
0.44
Sift
Benign
0.19
T;.;T;T;T;.;T;T;T;T
Sift4G
Benign
0.28
T;T;T;T;T;T;T;T;T;T
Polyphen
0.99
D;D;.;D;.;.;.;.;.;.
Vest4
0.67
MutPred
0.52
Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);Loss of helix (P = 0.028);
MVP
0.78
MPC
1.3
ClinPred
0.93
D
GERP RS
3.6
Varity_R
0.55
gMVP
0.58

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-88799344; API