rs6339

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.1838G>T(p.Gly613Val) variant causes a missense change. The variant allele was found at a frequency of 0.0533 in 1,613,774 control chromosomes in the GnomAD database, including 2,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 146 hom., cov: 32)

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: 3.65

Publications

44 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0029589236).

BP6

Variant 1-156879154-G-T is Benign according to our data. Variant chr1-156879154-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 12308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.1838G>T	p.Gly613Val	missense_variant	Exon 15 of 17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.1820G>T	p.Gly607Val	missense_variant	Exon 14 of 16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.1730G>T	p.Gly577Val	missense_variant	Exon 15 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.1838G>T	p.Gly613Val	missense_variant	Exon 15 of 17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.0377

AC:

5726

AN:

152068

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.0686

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0570

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0573

Gnomad OTH

AF:

0.0402

GnomAD2 exomes

AF:

0.0417

AC:

10381

AN:

249090

AF XY:

0.0446

show subpopulations

Gnomad AFR exome

AF:

0.00860

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0635

Gnomad EAS exome

AF:

0.000272

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0555

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0550

AC:

80333

AN:

1461588

Hom.:

2511

Cov.:

AF XY:

0.0554

AC XY:

40280

AN XY:

727104

show subpopulations

African (AFR)

AF:

0.00810

AC:

271

AN:

33472

American (AMR)

AF:

0.0244

AC:

1093

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0647

AC:

1690

AN:

26126

East Asian (EAS)

AF:

0.000227

AC:

AN:

39694

South Asian (SAS)

AF:

0.0569

AC:

4907

AN:

86230

European-Finnish (FIN)

AF:

0.0300

AC:

1602

AN:

53414

Middle Eastern (MID)

AF:

0.0462

AC:

265

AN:

5730

European-Non Finnish (NFE)

AF:

0.0605

AC:

67283

AN:

1111828

Other (OTH)

AF:

0.0532

AC:

3213

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.451

Heterozygous variant carriers

4167

8333

12500

16666

20833

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2514

5028

7542

10056

12570

<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:

5723

AN:

152186

Hom.:

146

Cov.:

AF XY:

0.0352

AC XY:

2619

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.0104

AC:

432

AN:

41536

American (AMR)

AF:

0.0309

AC:

472

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0686

AC:

238

AN:

3468

East Asian (EAS)

AF:

0.000193

AC:

AN:

5176

South Asian (SAS)

AF:

0.0568

AC:

273

AN:

4806

European-Finnish (FIN)

AF:

0.0262

AC:

278

AN:

10602

Middle Eastern (MID)

AF:

0.0340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0573

AC:

3896

AN:

67984

Other (OTH)

AF:

0.0397

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

287

575

862

1150

1437

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:

0.0498

Hom.:

767

Bravo

AF:

0.0366

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0586

AC:

226

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0603

AC:

519

ExAC

AF:

0.0421

AC:

5116

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0536

EpiControl

AF:

0.0556

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

Jan 01, 2019

Institute of Human Genetics, University of Leipzig Medical Center

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 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

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

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. -

Jun 10, 2021

Genome-Nilou Lab

Significance: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

- -

not specified

Benign:7

Clinical Genetics, Academic Medical Center

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

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

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

- -

May 23, 2014

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

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:3

Oct 05, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

0.099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

.;.;D;D

Eigen

Benign

-0.019

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.4

.;.;L;.

PhyloP100

3.7

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.13, 0.38

.;B;B;.

Vest4

0.20

MPC

0.48

ClinPred

0.018

GERP RS

3.4

Varity_R

0.34

gMVP

0.72

Mutation Taster

=56/44

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