chr1-156880036-C-T
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PP3_StrongPP5_Moderate
The NM_002529.4(NTRK1):c.2084C>T(p.Pro695Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,538 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. P695P) has been classified as Likely benign.
Frequency
Consequence
NM_002529.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.2084C>T | p.Pro695Leu | missense_variant | 16/17 | ENST00000524377.7 | |
NTRK1 | NM_001012331.2 | c.2066C>T | p.Pro689Leu | missense_variant | 15/16 | ||
NTRK1 | NM_001007792.1 | c.1976C>T | p.Pro659Leu | missense_variant | 16/17 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.2084C>T | p.Pro695Leu | missense_variant | 16/17 | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.00000658 AC: 1AN: 152028Hom.: 0 Cov.: 31
GnomAD4 exome AF: 0.0000123 AC: 18AN: 1461392Hom.: 0 Cov.: 32 AF XY: 0.0000110 AC XY: 8AN XY: 727008
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152146Hom.: 0 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74388
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Pathogenic:3
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 19, 2000 | - - |
Likely pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Jul 14, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jul 16, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 689 of the NTRK1 protein (p.Pro689Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with congenital insensitivity to pain with anhidrosis (PMID: 10861667, 30774415). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 12310). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NTRK1 protein function. For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at