NM_002529.4:c.865C>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002529.4(NTRK1):c.865C>A(p.Gln289Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00134 in 1,610,930 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q289H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0011 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0014 ( 2 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:7

Conservation

PhyloP100: -0.504

Publications

14 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: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
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 -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01085344).

BP6

Variant 1-156873647-C-A is Benign according to our data. Variant chr1-156873647-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 245652.

BS2

High Homozygotes in GnomAdExome4 at 2 AR,AD gene

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	UniProt
NTRK1	NM_002529.4	MANE Select	c.865C>A	p.Gln289Lys	missense	Exon 8 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.865C>A	p.Gln289Lys	missense	Exon 8 of 16	NP_001012331.1	P04629-2
NTRK1	NM_001007792.1		c.775C>A	p.Gln259Lys	missense	Exon 9 of 17	NP_001007793.1	P04629-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NTRK1	ENST00000524377.7	TSL:1 MANE Select	c.865C>A	p.Gln289Lys	missense	Exon 8 of 17	ENSP00000431418.1	P04629-1
NTRK1	ENST00000368196.7	TSL:1	c.865C>A	p.Gln289Lys	missense	Exon 8 of 16	ENSP00000357179.3	P04629-2
NTRK1	ENST00000956587.1		c.732C>A	p.Cys244*	stop_gained	Exon 7 of 13	ENSP00000626646.1

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152130

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00221

Gnomad OTH

AF:

0.00143

GnomAD2 exomes

AF:

0.000879

AC:

214

AN:

243374

AF XY:

0.000939

show subpopulations

Gnomad AFR exome

AF:

0.000136

Gnomad AMR exome

AF:

0.000582

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000240

Gnomad NFE exome

AF:

0.00166

Gnomad OTH exome

AF:

0.000839

GnomAD4 exome

AF:

0.00136

AC:

1985

AN:

1458682

Hom.:

Cov.:

AF XY:

0.00133

AC XY:

968

AN XY:

725644

show subpopulations

African (AFR)

AF:

0.0000898

AC:

AN:

33398

American (AMR)

AF:

0.000604

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.000115

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.000379

AC:

AN:

52784

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4220

European-Non Finnish (NFE)

AF:

0.00169

AC:

1875

AN:

1111590

Other (OTH)

AF:

0.000947

AC:

AN:

60164

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

102

205

307

410

512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

132

198

264

330

<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:

0.00114

AC:

174

AN:

152248

Hom.:

Cov.:

AF XY:

0.000967

AC XY:

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.000168

AC:

AN:

41558

American (AMR)

AF:

0.000654

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00221

AC:

150

AN:

68004

Other (OTH)

AF:

0.00142

AC:

AN:

2114

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

Genome Het

Genome 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

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.00105

TwinsUK

AF:

0.000809

AC:

ALSPAC

AF:

0.00130

AC:

ESP6500AA

AF:

0.000230

AC:

ESP6500EA

AF:

0.00188

AC:

ExAC

AF:

0.000867

AC:

105

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00131

EpiControl

AF:

0.00107

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Hereditary insensitivity to pain with anhidrosis (4)

not provided (3)

Hereditary cancer (1)

Inborn genetic diseases (1)

not specified (1)

NTRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.61

CADD

Benign

3.3

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

Eigen

Benign

-0.86

Eigen_PC

Benign

-0.77

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.60

M_CAP

Benign

0.0092

MetaRNN

Benign

0.011

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.69

PhyloP100

-0.50

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.11

REVEL

Benign

0.077

Sift

Benign

0.37

Sift4G

Benign

0.39

Polyphen

0.011

Vest4

0.17

MVP

0.66

MPC

0.31

ClinPred

0.023

GERP RS

3.0

Varity_R

0.26

gMVP

0.63

Mutation Taster

=97/3

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over