1-156879126-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_002529.4(NTRK1):c.1810C>T(p.His604Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,612 control chromosomes in the GnomAD database, including 2,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H604H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 147 hom., cov: 31)

Exomes 𝑓: 0.055 ( 2511 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:17O:1

Conservation

PhyloP100: 7.83

Publications

56 publications found

Variant links:

COSMIC-nc: COSV62324956

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.007919282).

BP6

Variant 1-156879126-C-T is Benign according to our data. Variant chr1-156879126-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 37077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NTRK1	NM_002529.4 link	c.1810C>T	p.His604Tyr	missense_variant	Exon 15 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 link	c.1792C>T	p.His598Tyr	missense_variant	Exon 14 of 16		NP_001012331.1
NTRK1	NM_001007792.1 link	c.1702C>T	p.His568Tyr	missense_variant	Exon 15 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.1810C>T	p.His604Tyr	missense_variant	Exon 15 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5720

AN:

152056

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0687

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0564

Gnomad FIN

AF:

0.0263

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0572

Gnomad OTH

AF:

0.0402

GnomAD2 exomes

AF:

0.0416

AC:

10359

AN:

248732

AF XY:

0.0446

show subpopulations

Gnomad AFR exome

AF:

0.00851

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0636

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.0554

Gnomad OTH exome

AF:

0.0505

GnomAD4 exome

AF:

0.0549

AC:

80241

AN:

1461438

Hom.:

2511

Cov.:

AF XY:

0.0553

AC XY:

40229

AN XY:

727022

show subpopulations

African (AFR)

AF:

0.00810

AC:

271

AN:

33474

American (AMR)

AF:

0.0245

AC:

1094

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0647

AC:

1691

AN:

26132

East Asian (EAS)

AF:

0.000227

AC:

AN:

39698

South Asian (SAS)

AF:

0.0571

AC:

4921

AN:

86222

European-Finnish (FIN)

AF:

0.0299

AC:

1598

AN:

53408

Middle Eastern (MID)

AF:

0.0472

AC:

265

AN:

5610

European-Non Finnish (NFE)

AF:

0.0604

AC:

67183

AN:

1111822

Other (OTH)

AF:

0.0532

AC:

3209

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

3965

7930

11894

15859

19824

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2512

5024

7536

10048

12560

<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:

0.0376

AC:

5717

AN:

152174

Hom.:

147

Cov.:

AF XY:

0.0351

AC XY:

2613

AN XY:

74394

show subpopulations

African (AFR)

AF:

0.0104

AC:

433

AN:

41512

American (AMR)

AF:

0.0309

AC:

473

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0687

AC:

238

AN:

3466

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0562

AC:

270

AN:

4802

European-Finnish (FIN)

AF:

0.0263

AC:

279

AN:

10608

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0572

AC:

3890

AN:

67992

Other (OTH)

AF:

0.0398

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

271

542

813

1084

1355

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

148

222

296

370

<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:

0.0506

Hom.:

617

Bravo

AF:

0.0366

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0584

AC:

225

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.0605

AC:

520

ExAC

AF:

0.0422

AC:

5125

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0534

EpiControl

AF:

0.0555

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:17Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Benign:7Other:1

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 28, 2019

Mendelics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 02, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 17, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:research

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Likely benign

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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

not specified

Benign:6

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 01, 2017

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Dec 10, 2021

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 16, 2025

Laboratory of Genetics, Children's Clinical University Hospital Latvia

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:4

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Mar 03, 2015

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27884173, 10330344, 21228398, 20981092, 19435634, 11719521, 18780967, 11159935, 22995991, 20003389) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Oct 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial medullary thyroid carcinoma

Pathogenic:1

Aug 01, 1999

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.33

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.0079

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.3

.;.;L;.

PhyloP100

7.8

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.99, 0.99

.;D;D;.

Vest4

0.61

MPC

0.89

ClinPred

0.018

GERP RS

4.4

Varity_R

0.96

gMVP

0.68

Mutation Taster

=21/79

polymorphism (auto)

(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