chr1-156881516-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002529.4(NTRK1):​c.2265G>C​(p.Glu755Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E755E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

NTRK1
NM_002529.4 missense

Scores

1
4
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.08
Variant links:
Genes affected
NTRK1 (HGNC:8031): (neurotrophic receptor tyrosine kinase 1) This gene encodes a member of the neurotrophic tyrosine kinase receptor (NTKR) family. This kinase is a membrane-bound receptor that, upon neurotrophin binding, phosphorylates itself and members of the MAPK pathway. The presence of this kinase leads to cell differentiation and may play a role in specifying sensory neuron subtypes. Mutations in this gene have been associated with congenital insensitivity to pain, anhidrosis, self-mutilating behavior, cognitive disability and cancer. Alternate transcriptional splice variants of this gene have been found, but only three have been characterized to date. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM1
In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 70 pathogenic changes around while only 22 benign (76%) in NM_002529.4
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.23543039).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NTRK1NM_002529.4 linkc.2265G>C p.Glu755Asp missense_variant 17/17 ENST00000524377.7 NP_002520.2 P04629-1
NTRK1NM_001012331.2 linkc.2247G>C p.Glu749Asp missense_variant 16/16 NP_001012331.1 P04629-2X5DR71
NTRK1NM_001007792.1 linkc.2157G>C p.Glu719Asp missense_variant 17/17 NP_001007793.1 P04629-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NTRK1ENST00000524377.7 linkc.2265G>C p.Glu755Asp missense_variant 17/171 NM_002529.4 ENSP00000431418.1 P04629-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.015
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.70
.;.;D;D
Eigen
Benign
-0.25
Eigen_PC
Benign
-0.097
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.80
T;T;T;T
M_CAP
Benign
0.033
D
MetaRNN
Benign
0.24
T;T;T;T
MetaSVM
Benign
-0.79
T
MutationAssessor
Benign
0.81
.;.;L;.
PrimateAI
Uncertain
0.69
T
PROVEAN
Benign
-2.1
N;N;N;N
REVEL
Benign
0.29
Sift
Benign
0.10
T;T;T;T
Sift4G
Benign
0.095
T;T;T;T
Polyphen
0.0, 0.0010
.;B;B;.
Vest4
0.25
MutPred
0.45
.;.;Loss of glycosylation at P753 (P = 0.0799);.;
MVP
0.90
MPC
0.22
ClinPred
0.72
D
GERP RS
3.1
Varity_R
0.39
gMVP
0.59

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-156851308; API