Genetic Variant NM_002529.4:c.2339G>A (chr1-156881590-G-A) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 2P and 9B. PM5BP4_StrongBP6BS2

The NM_002529.4(NTRK1):c.2339G>A(p.Arg780Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,611,386 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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. R780W) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0043 ( 7 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 36 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 0.472

Publications

33 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 -7 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-156881590-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 12303.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (MetaRNN=0.012337536).

BP6

Variant 1-156881590-G-A is Benign according to our data. Variant chr1-156881590-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 235534.

BS2

High Homozygotes in GnomAd4 at 7 AD,AR 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.2339G>A	p.Arg780Gln	missense	Exon 17 of 17	NP_002520.2
NTRK1	NM_001012331.2		c.2321G>A	p.Arg774Gln	missense	Exon 16 of 16	NP_001012331.1	P04629-2
NTRK1	NM_001007792.1		c.2231G>A	p.Arg744Gln	missense	Exon 17 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.2339G>A	p.Arg780Gln	missense	Exon 17 of 17	ENSP00000431418.1	P04629-1
NTRK1	ENST00000368196.7	TSL:1	c.2321G>A	p.Arg774Gln	missense	Exon 16 of 16	ENSP00000357179.3	P04629-2
NTRK1	ENST00000358660.3	TSL:2	c.2330G>A	p.Arg777Gln	missense	Exon 16 of 16	ENSP00000351486.3	J3KP20

Frequencies

GnomAD3 genomes

AF:

0.00434

AC:

660

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00752

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0114

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00607

Gnomad OTH

AF:

0.00574

GnomAD2 exomes

AF:

0.00480

AC:

1166

AN:

243110

AF XY:

0.00537

show subpopulations

Gnomad AFR exome

AF:

0.000716

Gnomad AMR exome

AF:

0.00279

Gnomad ASJ exome

AF:

0.000304

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00103

Gnomad NFE exome

AF:

0.00635

Gnomad OTH exome

AF:

0.00372

GnomAD4 exome

AF:

0.00583

AC:

8513

AN:

1459030

Hom.:

Cov.:

AF XY:

0.00613

AC XY:

4449

AN XY:

725604

show subpopulations

African (AFR)

AF:

0.000688

AC:

AN:

33438

American (AMR)

AF:

0.00274

AC:

122

AN:

44478

Ashkenazi Jewish (ASJ)

AF:

0.000576

AC:

AN:

26026

East Asian (EAS)

AF:

0.0000757

AC:

AN:

39626

South Asian (SAS)

AF:

0.0117

AC:

1004

AN:

85694

European-Finnish (FIN)

AF:

0.00165

AC:

AN:

52678

Middle Eastern (MID)

AF:

0.00699

AC:

AN:

5722

European-Non Finnish (NFE)

AF:

0.00623

AC:

6922

AN:

1111116

Other (OTH)

AF:

0.00493

AC:

297

AN:

60252

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

510

1019

1529

2038

2548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

262

524

786

1048

1310

<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:

0.00433

AC:

659

AN:

152356

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.00103

AC:

AN:

41590

American (AMR)

AF:

0.00751

AC:

115

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.0114

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.0136

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00607

AC:

413

AN:

68034

Other (OTH)

AF:

0.00568

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

105

140

175

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:

0.00535

Hom.:

Bravo

AF:

0.00383

TwinsUK

AF:

0.00755

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00465

AC:

ExAC

AF:

0.00489

AC:

593

Asia WGS

AF:

0.00462

AC:

AN:

3478

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 (6)

not specified (3)

not provided (2)

NTRK1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Uncertain

0.57

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.82

MetaRNN

Benign

0.012

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.59

PhyloP100

0.47

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

REVEL

Uncertain

0.34

Sift

Benign

0.23

Sift4G

Benign

0.45

Polyphen

0.0050

Vest4

0.28

MVP

0.79

MPC

0.30

ClinPred

0.0073

GERP RS

4.1

Varity_R

0.24

gMVP

0.65

Mutation Taster

=99/1

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

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