rs144901788

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:7B: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/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.1474G>A	p.Glu492Lys	missense_variant	12/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.1456G>A	p.Glu486Lys	missense_variant	11/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.1366G>A	p.Glu456Lys	missense_variant	12/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.1474G>A	p.Glu492Lys	missense_variant	12/17	1	NM_002529.4	P4	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:7Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2023	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: 22302274, 27058611, 32707200, 34426522, 33235206, 35101157) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NTRK1: PM2, PP3 -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 01, 2019	- -

Hereditary insensitivity to pain with anhidrosis

Uncertain:2Benign:1

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Oct 25, 2017	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. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

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

Jun 02, 2023

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

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

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

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

MutationTaster

Benign

1.0

D;D;D;D

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