NM_002529.4:c.16C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002529.4(NTRK1):c.16C>T(p.Arg6Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00434 in 1,495,226 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R6R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0036 ( 2 hom., cov: 33)

Exomes 𝑓: 0.0044 ( 13 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:11

Conservation

PhyloP100: 0.668

Publications

15 publications found

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01958999).

BP6

Variant 1-156860950-C-T is Benign according to our data. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386. Variant chr1-156860950-C-T is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 234386.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.16C>T	p.Arg6Trp	missense_variant	Exon 1 of 17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.16C>T	p.Arg6Trp	missense_variant	Exon 1 of 16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.123-3404C>T		intron_variant	Intron 2 of 16		NP_001007793.1	P04629-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.16C>T	p.Arg6Trp	missense_variant	Exon 1 of 17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.00358

AC:

544

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000677

Gnomad AMI

AF:

0.0209

Gnomad AMR

AF:

0.00242

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00737

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00544

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00325

AC:

308

AN:

94852

AF XY:

0.00318

show subpopulations

Gnomad AFR exome

AF:

0.00196

Gnomad AMR exome

AF:

0.000941

Gnomad ASJ exome

AF:

0.000928

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00613

Gnomad NFE exome

AF:

0.00586

Gnomad OTH exome

AF:

0.00411

GnomAD4 exome

AF:

0.00443

AC:

5946

AN:

1343160

Hom.:

Cov.:

AF XY:

0.00436

AC XY:

2886

AN XY:

661604

show subpopulations

African (AFR)

AF:

0.000587

AC:

AN:

27272

American (AMR)

AF:

0.00121

AC:

AN:

30480

Ashkenazi Jewish (ASJ)

AF:

0.00123

AC:

AN:

23508

East Asian (EAS)

AF:

0.00

AC:

AN:

31612

South Asian (SAS)

AF:

0.00150

AC:

111

AN:

74144

European-Finnish (FIN)

AF:

0.00507

AC:

169

AN:

33352

Middle Eastern (MID)

AF:

0.000254

AC:

AN:

3944

European-Non Finnish (NFE)

AF:

0.00509

AC:

5414

AN:

1062876

Other (OTH)

AF:

0.00302

AC:

169

AN:

55972

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

338

677

1015

1354

1692

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

200

400

600

800

1000

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00358

AC:

544

AN:

152066

Hom.:

Cov.:

AF XY:

0.00355

AC XY:

264

AN XY:

74340

show subpopulations

African (AFR)

AF:

0.000675

AC:

AN:

41498

American (AMR)

AF:

0.00242

AC:

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5148

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00737

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00545

AC:

370

AN:

67950

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

101

135

169

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00311

Hom.:

Bravo

AF:

0.00283

ExAC

AF:

0.00150

AC:

Asia WGS

AF:

0.000578

AC:

AN:

3472

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Uncertain:2Benign:4

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

May 31, 2018

SIB Swiss Institute of Bioinformatics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:curation

This variant is interpreted as a Likely Benign, for Insensitivity to pain, congenital, with anhidrosis, in Autosomal Recessive manner. The following ACMG Tag(s) were applied: BP5 =>Variant found in a case with an alternate molecular basis for disease (PMID:22302274). BS1-Supporting => BS1 downgraded in strength to supporting. -

Nov 22, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 06, 2020

Natera, Inc.

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Clinical Genetics, Academic Medical Center

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 04, 2021

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27527004, 22302274, 26215504, 27535533, 32707200) -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jun 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

NTRK1: BS2 -

not specified

Benign:1

Sep 13, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

NTRK1-related disorder

Benign:1

Oct 25, 2019

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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). -

Inborn genetic diseases

Benign:1

Aug 28, 2019

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.33

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.32

.;T;T

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.33

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.82

T;T;T

M_CAP

Pathogenic

0.91

MetaRNN

Benign

0.020

T;T;T

MetaSVM

Benign

-0.60

MutationAssessor

Benign

1.6

L;L;.

PhyloP100

0.67

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.57

N;N;N

REVEL

Uncertain

0.35

Sift

Uncertain

0.0080

D;D;D

Sift4G

Uncertain

0.0090

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.42

MVP

0.92

MPC

0.45

ClinPred

0.021

GERP RS

4.2

PromoterAI

0.023

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.46

Mutation Taster

=94/6

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over