rs747855434
Variant summary
Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1PM2PP3
The NM_002529.4(NTRK1):c.2119G>A(p.Glu707Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,406 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
NTRK1
NM_002529.4 missense
NM_002529.4 missense
Scores
7
9
1
Clinical Significance
Conservation
PhyloP100: 9.74
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 5 ACMG points.
PM1
?
In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_002529.4
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.819
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.2119G>A | p.Glu707Lys | missense_variant | 16/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.2101G>A | p.Glu701Lys | missense_variant | 15/16 | ||
NTRK1 | NM_001007792.1 | c.2011G>A | p.Glu671Lys | missense_variant | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.2119G>A | p.Glu707Lys | missense_variant | 16/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 151922Hom.: 0 Cov.: 30
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GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251100Hom.: 0 AF XY: 0.0000147 AC XY: 2AN XY: 135802
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461484Hom.: 0 Cov.: 32 AF XY: 0.0000124 AC XY: 9AN XY: 727064
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:4
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Uncertain:3
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2021 | This sequence change replaces glutamic acid with lysine at codon 701 of the NTRK1 protein (p.Glu701Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs747855434, ExAC 0.006%). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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 | May 18, 2021 | - - |
Premature ovarian failure Pathogenic:1
Likely pathogenic, criteria provided, single submitter | research | Medical Cytogenetics and Molecular Genetics Laboratory, IRCCS Istituto Auxologico Italiano | Mar 02, 2020 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Mar 07, 2024 | Variant summary: NTRK1 c.2101G>A (p.Glu701Lys) results in a conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 1.2e-05 in 251100 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2101G>A has been reported in the literature in one individual affected with primary ovarian insufficiency (Bestetti_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Insensitivity To Pain With Anhidrosis. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication have been ascertained in the context of this evaluation (PMID: 34480478). ClinVar contains an entry for this variant (Variation ID: 526718). Based on the evidence outlined above, the variant was classified as uncertain significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.34, 0.95
.;B;P;.
Vest4
MutPred
0.59
.;.;Gain of ubiquitination at E707 (P = 0.0369);.;
MVP
MPC
0.79
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at