rs137979116
Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2
The NM_002529.4(NTRK1):c.865C>A(p.Gln289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,610,930 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q289H) has been classified as Likely benign.
Frequency
Consequence
NM_002529.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -9 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.865C>A | p.Gln289Lys | missense_variant | 8/17 | ENST00000524377.7 | NP_002520.2 | |
NTRK1 | NM_001012331.2 | c.865C>A | p.Gln289Lys | missense_variant | 8/16 | NP_001012331.1 | ||
NTRK1 | NM_001007792.1 | c.775C>A | p.Gln259Lys | missense_variant | 9/17 | NP_001007793.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.865C>A | p.Gln289Lys | missense_variant | 8/17 | 1 | NM_002529.4 | ENSP00000431418.1 |
Frequencies
GnomAD3 genomes AF: 0.00114 AC: 174AN: 152130Hom.: 1 Cov.: 31
GnomAD3 exomes AF: 0.000879 AC: 214AN: 243374Hom.: 0 AF XY: 0.000939 AC XY: 125AN XY: 133154
GnomAD4 exome AF: 0.00136 AC: 1985AN: 1458682Hom.: 2 Cov.: 32 AF XY: 0.00133 AC XY: 968AN XY: 725644
GnomAD4 genome AF: 0.00114 AC: 174AN: 152248Hom.: 1 Cov.: 31 AF XY: 0.000967 AC XY: 72AN XY: 74450
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Uncertain:2Benign:2
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | Apr 17, 2020 | - - |
Uncertain significance, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Oct 20, 2023 | The NTRK1 c.865C>A; p.Gln289Lys variant (rs137979116), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 245652). This variant is found in the non-Finnish European population with an allele frequency of 0.2% (227/124,316 alleles, including 1 homozygote) in the Genome Aggregation Database. The glutamine at codon 289 is moderately conserved, and computational analyses predict that this variant is neutral (REVEL: 0.077). However, given the lack of clinical and functional data, the significance of the p.Gln289Lys variant is uncertain at this time. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Jan 29, 2024 | - - |
not provided Uncertain:1Benign:1
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Dec 21, 2020 | In silico analysis supports that this missense variant does not alter protein structure/function - |
Uncertain significance, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2022 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Sep 08, 2021 | The p.Q289K variant (also known as c.865C>A), located in coding exon 8 of the NTRK1 gene, results from a C to A substitution at nucleotide position 865. The glutamine at codon 289 is replaced by lysine, an amino acid with similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Athena Diagnostics | Mar 31, 2021 | - - |
NTRK1-related disorder Benign:1
Likely benign, no assertion criteria provided | clinical testing | PreventionGenetics, part of Exact Sciences | May 09, 2022 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Hereditary cancer Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Mendelics | Jan 23, 2024 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at