chr1-156881473-C-T
Variant summary
Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2
The NM_002529.4(NTRK1):c.2222C>T(p.Thr741Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000336 in 1,575,974 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T741T) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000033 ( 0 hom. )
Consequence
NTRK1
NM_002529.4 missense
NM_002529.4 missense
Scores
7
8
2
Clinical Significance
Conservation
PhyloP100: 6.08
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 4 ACMG points.
PM1
?
In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 69 pathogenic changes around while only 22 benign (76%) in NM_002529.4
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.2222C>T | p.Thr741Met | missense_variant | 17/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.2204C>T | p.Thr735Met | missense_variant | 16/16 | ||
NTRK1 | NM_001007792.1 | c.2114C>T | p.Thr705Met | missense_variant | 17/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.2222C>T | p.Thr741Met | missense_variant | 17/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.0000394 AC: 6AN: 152240Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000586 AC: 11AN: 187860Hom.: 0 AF XY: 0.0000595 AC XY: 6AN XY: 100850
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GnomAD4 exome AF: 0.0000330 AC: 47AN: 1423616Hom.: 0 Cov.: 31 AF XY: 0.0000312 AC XY: 22AN XY: 704758
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Uncertain:3
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 25, 2022 | This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 735 of the NTRK1 protein (p.Thr735Met). This variant is present in population databases (rs145081333, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 452208). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Sep 22, 2017 | A variant of uncertain significance has been identified in the NTRK1 gene. The T735M variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The T735M variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The T735M variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. - |
Hereditary insensitivity to pain with anhidrosis;C1833921:Familial medullary thyroid carcinoma Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Uncertain
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Pathogenic
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.96, 1.0
.;D;D;.
Vest4
MVP
MPC
0.90
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
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Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at