rs121964870
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1PM2PP3PP5_Moderate
The NM_002529.4(NTRK1):c.1759A>G(p.Met587Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: not found (cov: 33)
Consequence
NTRK1
NM_002529.4 missense
NM_002529.4 missense
Scores
5
10
2
Clinical Significance
Conservation
PhyloP100: 7.48
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 Likely_pathogenic. Variant got 7 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;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.823
PP5
?
Variant 1-156876526-A-G is Pathogenic according to our data. Variant chr1-156876526-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12312.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156876526-A-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.1759A>G | p.Met587Val | missense_variant | 14/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.1741A>G | p.Met581Val | missense_variant | 13/16 | ||
NTRK1 | NM_001007792.1 | c.1651A>G | p.Met551Val | missense_variant | 14/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.1759A>G | p.Met587Val | missense_variant | 14/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 genomes
?
Cov.:
33
GnomAD4 exome Cov.: 34
GnomAD4 exome
Cov.:
34
GnomAD4 genome ? Cov.: 33
GnomAD4 genome
?
Cov.:
33
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Oct 01, 2002 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | May 16, 2019 | For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect NTRK1 protein function (PMID: 12406349). This variant has been observed to segregate with hereditary sensory and autonomic neuropathy in a family (PMID: 0233776). ClinVar contains an entry for this variant (Variation ID: 12312). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 581 of the NTRK1 protein (p.Met581Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D
M_CAP
Benign
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Uncertain
T
MutationTaster
Benign
A;A;A;A
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
0.51, 0.99
.;P;D;.
Vest4
MutPred
0.61
.;.;Loss of phosphorylation at Y591 (P = 0.2187);.;
MVP
MPC
0.88
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at