chr1-156881548-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_002529.4(NTRK1):c.2297G>A(p.Arg766Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000162 in 1,608,524 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R766W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000015 ( 1 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: 10.0

Publications

3 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: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_002529.4

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.2297G>A	p.Arg766Gln	missense	Exon 17 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.2279G>A	p.Arg760Gln	missense	Exon 16 of 16	NP_001012331.1
NTRK1	NM_001007792.1		c.2189G>A	p.Arg730Gln	missense	Exon 17 of 17	NP_001007793.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.2297G>A	p.Arg766Gln	missense	Exon 17 of 17	ENSP00000431418.1
NTRK1	ENST00000368196.7	TSL:1	c.2279G>A	p.Arg760Gln	missense	Exon 16 of 16	ENSP00000357179.3
NTRK1	ENST00000358660.3	TSL:2	c.2288G>A	p.Arg763Gln	missense	Exon 16 of 16	ENSP00000351486.3

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152256

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000126

AC:

AN:

237846

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.0000671

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000151

AC:

AN:

1456268

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

723972

show subpopulations

African (AFR)

AF:

0.0000299

AC:

AN:

33390

American (AMR)

AF:

0.00

AC:

AN:

44094

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25958

East Asian (EAS)

AF:

0.0000254

AC:

AN:

39442

South Asian (SAS)

AF:

0.0000822

AC:

AN:

85194

European-Finnish (FIN)

AF:

0.0000191

AC:

AN:

52406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00000631

AC:

AN:

1109894

Other (OTH)

AF:

0.0000831

AC:

AN:

60136

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<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:

0.0000263

AC:

AN:

152256

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74382

show subpopulations

African (AFR)

AF:

0.0000482

AC:

AN:

41474

American (AMR)

AF:

0.00

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.0000580

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary insensitivity to pain with anhidrosis (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Pathogenic

0.21

BayesDel_noAF

Uncertain

0.070

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

Eigen

Uncertain

0.49

Eigen_PC

Uncertain

0.59

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.043

MetaRNN

Uncertain

0.45

MetaSVM

Uncertain

0.40

MutationAssessor

Benign

0.28

PhyloP100

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.60

Sift

Uncertain

0.011

Sift4G

Benign

0.082

Polyphen

0.064

Vest4

0.59

MutPred

0.43

Loss of MoRF binding (P = 0.0302)

MVP

0.95

MPC

0.86

ClinPred

0.74

GERP RS

5.0

Varity_R

0.65

gMVP

0.67

Mutation Taster

=23/77

disease causing

(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

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