Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002529.4(NTRK1):c.2052A>G(p.Gly684Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00605 in 1,612,412 control chromosomes in the GnomAD database, including 479 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. G684G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.031 ( 244 hom., cov: 31)

Exomes 𝑓: 0.0035 ( 235 hom. )

Consequence

NTRK1
NM_002529.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -1.46

Publications

4 publications found

Variant links:

COSMIC-nc: COSV104662707

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.62).

BP6

Variant 1-156880004-A-G is Benign according to our data. Variant chr1-156880004-A-G is described in ClinVar as Benign. ClinVar VariationId is 138566.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.46 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.103 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002529.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	NM_002529.4	MANE Select	c.2052A>G	p.Gly684Gly	synonymous	Exon 16 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.2034A>G	p.Gly678Gly	synonymous	Exon 15 of 16	NP_001012331.1
NTRK1	NM_001007792.1		c.1944A>G	p.Gly648Gly	synonymous	Exon 16 of 17	NP_001007793.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.2052A>G	p.Gly684Gly	synonymous	Exon 16 of 17	ENSP00000431418.1
NTRK1	ENST00000368196.7	TSL:1	c.2034A>G	p.Gly678Gly	synonymous	Exon 15 of 16	ENSP00000357179.3
NTRK1	ENST00000358660.3	TSL:2	c.2043A>G	p.Gly681Gly	synonymous	Exon 15 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes

AF:

0.0305

AC:

4623

AN:

151660

Hom.:

244

Cov.:

show subpopulations

Gnomad AFR

AF:

0.105

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0131

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00104

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.000280

Gnomad OTH

AF:

0.0216

GnomAD2 exomes

AF:

0.00856

AC:

2135

AN:

249404

AF XY:

0.00638

show subpopulations

Gnomad AFR exome

AF:

0.112

Gnomad AMR exome

AF:

0.00602

Gnomad ASJ exome

AF:

0.00338

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.0000954

Gnomad NFE exome

AF:

0.000487

Gnomad OTH exome

AF:

0.00509

GnomAD4 exome

AF:

0.00350

AC:

5115

AN:

1460634

Hom.:

235

Cov.:

AF XY:

0.00310

AC XY:

2253

AN XY:

726692

show subpopulations

African (AFR)

AF:

0.113

AC:

3794

AN:

33476

American (AMR)

AF:

0.00666

AC:

298

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00253

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000614

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52224

Middle Eastern (MID)

AF:

0.0200

AC:

115

AN:

5764

European-Non Finnish (NFE)

AF:

0.000247

AC:

275

AN:

1111984

Other (OTH)

AF:

0.00851

AC:

514

AN:

60370

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

263

526

789

1052

1315

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

264

396

528

660

<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:

0.0305

AC:

4633

AN:

151778

Hom.:

244

Cov.:

AF XY:

0.0291

AC XY:

2162

AN XY:

74178

show subpopulations

African (AFR)

AF:

0.105

AC:

4348

AN:

41344

American (AMR)

AF:

0.0131

AC:

200

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5128

South Asian (SAS)

AF:

0.000833

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10552

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000280

AC:

AN:

67920

Other (OTH)

AF:

0.0214

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

192

385

577

770

962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

132

176

220

<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:

0.0169

Hom.:

Bravo

AF:

0.0348

Asia WGS

AF:

0.00664

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000652

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary insensitivity to pain with anhidrosis (4)

not specified (3)

not provided (1)

NTRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.62

CADD

Benign

9.8

(source)

DANN

Benign

0.75

PhyloP100

-1.5

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over