rs144901788

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_002529.4(NTRK1):c.1474G>A(p.Glu492Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00069 in 1,613,264 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00038 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00072 ( 1 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8B:1

Conservation

PhyloP100: 6.64

Variant links:

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]

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.1474G>A	p.Glu492Lys	missense_variant	Exon 12 of 17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.1456G>A	p.Glu486Lys	missense_variant	Exon 11 of 16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.1366G>A	p.Glu456Lys	missense_variant	Exon 12 of 17		NP_001007793.1	P04629-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.1474G>A	p.Glu492Lys	missense_variant	Exon 12 of 17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.000376

AC:

AN:

151796

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000194

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000706

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000454

AC:

114

AN:

250934

Hom.:

AF XY:

0.000361

AC XY:

AN XY:

135648

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000141

Gnomad NFE exome

AF:

0.000845

Gnomad OTH exome

AF:

0.000489

GnomAD4 exome

AF:

0.000723

AC:

1056

AN:

1461468

Hom.:

Cov.:

AF XY:

0.000696

AC XY:

506

AN XY:

727070

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000157

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000170

Gnomad4 NFE exome

AF:

0.000902

Gnomad4 OTH exome

AF:

0.000530

GnomAD4 genome

AF:

0.000376

AC:

AN:

151796

Hom.:

Cov.:

AF XY:

0.000324

AC XY:

AN XY:

74098

show subpopulations

Gnomad4 AFR

AF:

0.000194

Gnomad4 AMR

AF:

0.0000656

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000706

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000626

Hom.:

Bravo

AF:

0.000344

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00116

AC:

ExAC

AF:

0.000519

AC:

EpiCase

AF:

0.000327

EpiControl

AF:

0.000533

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Uncertain:3Benign:1

Apr 23, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NTRK1 c.1456G>A; p.Glu486Lys variant (rs144901788), also known as p.Glu492Lys in transcript NM_002529.3, is reported in the literature in a homozygous individual affected with hereditary sensory and autonomic neuropathy (Davidson 2012). This variant was also found in heterozygous individuals with uveitis (Li 2021) or bipolar disorder (Nakajima 2020), and it was found trans to a second NTRK1 missense variant in an individual with atrioventricular septal heart defect (Priest 2016). This variant is found in the non-Finnish European population with an overall allele frequency of 0.08% (105/128976 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses predict that this variant is deleterious (REVEL: 0.757). Neural stem cells expressing the variant protein have reduced neurite outgrowth, and mice expressing the variant protein in brain exhibit depression-like behavior (Nakajima 2020); however, the relevance of these assays to neuropathy is unclear. Due to limited information, the clinical significance of the p.Glu486Lys variant is uncertain at this time. References: Davidson et al. Frequency of mutations in the genes associated with hereditary sensory and autonomic neuropathy in a UK cohort. J Neurol. 2012 Aug;259(8):1673-85. PMID: 22302274. Li et al. Whole-Exome Sequencing of Patients With Posterior Segment Uveitis. Am J Ophthalmol. 2021 Jan;221:246-259. PMID: 32707200. Nakajima et al. Ntrk1 mutation co-segregating with bipolar disorder and inherited kidney disease in a multiplex family causes defects in neuronal growth and depression-like behavior in mice. Transl Psychiatry. 2020 Nov 24;10(1):407. PMID: 33235206. Priest et al. De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects. PLoS Genet. 2016 Apr 8;12(4):e1005963. PMID: 27058611. -

Oct 25, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Sep 16, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Uncertain:3

Apr 01, 2019

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 15, 2025

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27058611, 22302274, 32707200, 34426522, 33235206, 35101157) -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

NTRK1: PM2, PP3 -

not specified

Uncertain:1

Jun 02, 2023

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: NTRK1 c.1456G>A (p.Glu486Lys) results in a conservative amino acid change in 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 0.00045 in 250934 control chromosomes (gnomAD). This frequency is not significantly higher than estimated for a pathogenic variant in NTRK1 causing Hereditary Insensitivity To Pain With Anhidrosis (0.00045 vs 0.0011), allowing no conclusion about variant significance. c.1456G>A has been reported in the literature in individuals affected with sensory and autonomic neuropathy, presumed ocular histoplasmosis syndrome, as well as in a large pedigree, in which bipolar disorder co-segregated with autosomal dominant tubulointerstitial kidney disease (Davidson_2012, Li_2020, Nakajima_2020). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Insensitivity To Pain With Anhidrosis. At least one functional study showed E492K NSCs (neural stem cells) had reduced neurite outgrowth and a conditional knock-in mouse line showed depression-like behavior in the tail suspension test following challenge by physostigmine, a cholinesterase inhibitor (Nakajima_2020). The following publications have been ascertained in the context of this evaluation (PMID: 22302274, 32707200, 33235206). Five ClinVar submitters (evaluation after 2014) cite this variant as uncertain significance (n=4) and likely benign (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease

Uncertain:1

Inherited Neuropathy Consortium

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.43

BayesDel_addAF

Uncertain

0.10

BayesDel_noAF

Pathogenic

0.30

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.77

.;.;D;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.57

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D;D;D

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.54

D;D;D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Uncertain

2.7

.;.;M;.

PrimateAI

Uncertain

0.77

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Pathogenic

0.76

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.030

D;D;D;D

Polyphen

0.069, 1.0

.;B;D;.

Vest4

0.85

MVP

0.96

MPC

0.36

ClinPred

0.075

GERP RS

4.7

Varity_R

0.84

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over