1-156868640-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.710C>T(p.Thr237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,550,790 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T237A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 72 hom., cov: 33)

Exomes 𝑓: 0.0017 ( 60 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.347

Publications

9 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=0.002357781).

BP6

Variant 1-156868640-C-T is Benign according to our data. Variant chr1-156868640-C-T is described in ClinVar as Benign. ClinVar VariationId is 198111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 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.710C>T	p.Thr237Met	missense	Exon 6 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.710C>T	p.Thr237Met	missense	Exon 6 of 16	NP_001012331.1
NTRK1	NM_001007792.1		c.620C>T	p.Thr207Met	missense	Exon 7 of 17	NP_001007793.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.710C>T	p.Thr237Met	missense	Exon 6 of 17	ENSP00000431418.1
NTRK1	ENST00000368196.7	TSL:1	c.710C>T	p.Thr237Met	missense	Exon 6 of 16	ENSP00000357179.3
NTRK1	ENST00000358660.3	TSL:2	c.710C>T	p.Thr237Met	missense	Exon 6 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes

AF:

0.0164

AC:

2497

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0570

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00694

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000620

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.00909

GnomAD2 exomes

AF:

0.00401

AC:

619

AN:

154444

AF XY:

0.00317

show subpopulations

Gnomad AFR exome

AF:

0.0578

Gnomad AMR exome

AF:

0.00388

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000671

Gnomad OTH exome

AF:

0.00364

GnomAD4 exome

AF:

0.00170

AC:

2381

AN:

1398508

Hom.:

Cov.:

AF XY:

0.00149

AC XY:

1031

AN XY:

689830

show subpopulations

African (AFR)

AF:

0.0580

AC:

1832

AN:

31594

American (AMR)

AF:

0.00434

AC:

155

AN:

35708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.000379

AC:

AN:

79232

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48480

Middle Eastern (MID)

AF:

0.00339

AC:

AN:

5606

European-Non Finnish (NFE)

AF:

0.000102

AC:

110

AN:

1078982

Other (OTH)

AF:

0.00405

AC:

235

AN:

57988

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

158

316

474

632

790

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

116

174

232

290

<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:

0.0164

AC:

2500

AN:

152282

Hom.:

Cov.:

AF XY:

0.0157

AC XY:

1168

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0569

AC:

2363

AN:

41540

American (AMR)

AF:

0.00693

AC:

106

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000118

AC:

AN:

68014

Other (OTH)

AF:

0.00900

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

121

243

364

486

607

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.00770

Hom.:

Bravo

AF:

0.0185

ESP6500AA

AF:

0.0479

AC:

196

ESP6500EA

AF:

0.000623

AC:

ExAC

AF:

0.00316

AC:

225

Asia WGS

AF:

0.00289

AC:

AN:

3478

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 (7)

not provided (2)

not specified (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.55

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.55

Eigen

Benign

-0.11

Eigen_PC

Benign

-0.23

FATHMM_MKL

Benign

0.18

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.5

PhyloP100

0.35

PrimateAI

Benign

0.36

PROVEAN

Benign

-1.1

REVEL

Benign

0.046

Sift

Benign

0.14

Sift4G

Benign

0.19

Polyphen

1.0

Vest4

0.25

MVP

0.90

MPC

0.29

ClinPred

0.0054

GERP RS

2.5

Varity_R

0.035

gMVP

0.62

Mutation Taster

=94/6

polymorphism

(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

Computational scores

Splicing

Publications

Other links and lift over