1-156879203-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_002529.4(NTRK1):c.1887C>T(p.Ala629Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 1,613,480 control chromosomes in the GnomAD database, including 369,340 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A629A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.53 ( 25958 hom., cov: 31)

Exomes 𝑓: 0.67 ( 343382 hom. )

Consequence

NTRK1
NM_002529.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:10

Conservation

PhyloP100: -3.99

Publications

23 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.33).

BP6

Variant 1-156879203-C-T is Benign according to our data. Variant chr1-156879203-C-T is described in ClinVar as Benign. ClinVar VariationId is 138564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.719 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.1887C>T	p.Ala629Ala	synonymous_variant	Exon 15 of 17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.1869C>T	p.Ala623Ala	synonymous_variant	Exon 14 of 16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.1779C>T	p.Ala593Ala	synonymous_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.1887C>T	p.Ala629Ala	synonymous_variant	Exon 15 of 17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.533

AC:

80948

AN:

151840

Hom.:

25959

Cov.:

show subpopulations

Gnomad AFR

AF:

0.214

Gnomad AMI

AF:

0.711

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.750

Gnomad EAS

AF:

0.0503

Gnomad SAS

AF:

0.371

Gnomad FIN

AF:

0.731

Gnomad MID

AF:

0.671

Gnomad NFE

AF:

0.724

Gnomad OTH

AF:

0.556

GnomAD2 exomes

AF:

0.578

AC:

143744

AN:

248724

AF XY:

0.582

show subpopulations

Gnomad AFR exome

AF:

0.198

Gnomad AMR exome

AF:

0.575

Gnomad ASJ exome

AF:

0.751

Gnomad EAS exome

AF:

0.0396

Gnomad FIN exome

AF:

0.732

Gnomad NFE exome

AF:

0.724

Gnomad OTH exome

AF:

0.638

GnomAD4 exome

AF:

0.667

AC:

975001

AN:

1461522

Hom.:

343382

Cov.:

AF XY:

0.661

AC XY:

480752

AN XY:

727024

show subpopulations

African (AFR)

AF:

0.193

AC:

6460

AN:

33480

American (AMR)

AF:

0.578

AC:

25810

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

19605

AN:

26128

East Asian (EAS)

AF:

0.0457

AC:

1814

AN:

39688

South Asian (SAS)

AF:

0.398

AC:

34365

AN:

86246

European-Finnish (FIN)

AF:

0.733

AC:

39134

AN:

53370

Middle Eastern (MID)

AF:

0.603

AC:

3477

AN:

5766

European-Non Finnish (NFE)

AF:

0.726

AC:

806890

AN:

1111816

Other (OTH)

AF:

0.620

AC:

37446

AN:

60362

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

17599

35198

52797

70396

87995

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

19466

38932

58398

77864

97330

<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:

0.533

AC:

80961

AN:

151958

Hom.:

25958

Cov.:

AF XY:

0.526

AC XY:

39055

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.214

AC:

8866

AN:

41424

American (AMR)

AF:

0.558

AC:

8530

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.750

AC:

2603

AN:

3470

East Asian (EAS)

AF:

0.0506

AC:

261

AN:

5162

South Asian (SAS)

AF:

0.371

AC:

1783

AN:

4808

European-Finnish (FIN)

AF:

0.731

AC:

7724

AN:

10572

Middle Eastern (MID)

AF:

0.673

AC:

198

AN:

294

European-Non Finnish (NFE)

AF:

0.724

AC:

49181

AN:

67932

Other (OTH)

AF:

0.554

AC:

1168

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1484

2967

4451

5934

7418

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

660

1320

1980

2640

3300

<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:

0.661

Hom.:

48174

Bravo

AF:

0.512

Asia WGS

AF:

0.233

AC:

812

AN:

3478

EpiCase

AF:

0.716

EpiControl

AF:

0.717

ClinVar

Significance: Benign

Submissions summary: Uncertain:1Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1Benign:4

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

- -

Inherited Neuropathy Consortium

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 28, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary insensitivity to pain with anhidrosis

Benign:5

Jul 07, 2023

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 01, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.33

CADD

Benign

3.8

(source)

DANN

Benign

0.82

PhyloP100

-4.0

Mutation Taster

=98/2

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