rs35669708

Positions:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1PM5BP4_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. 14/20 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. R780P) has been classified as Pathogenic.

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

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 links:

NTRK1 (HGNC:):

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 70 pathogenic changes around while only 22 benign (76%) in NM_002529.4

PM5

Other missense variant is known to change same aminoacid residue: Variant chr1-156881590-G-C is described in ClinVar as [Pathogenic]. Clinvar id 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 id is 235534.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1, Benign=6}. Variant chr1-156881590-G-A is described in Lovd as [Benign].

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4 linkuse as main transcript	c.2339G>A	p.Arg780Gln	missense_variant	17/17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 linkuse as main transcript	c.2321G>A	p.Arg774Gln	missense_variant	16/16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 linkuse as main transcript	c.2231G>A	p.Arg744Gln	missense_variant	17/17		NP_001007793.1	P04629-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.2339G>A	p.Arg780Gln	missense_variant	17/17	1	NM_002529.4	ENSP00000431418.1		P04629-1

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

GnomAD3 exomes

AF:

0.00480

AC:

1166

AN:

243110

Hom.:

AF XY:

0.00537

AC XY:

710

AN XY:

132246

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 SAS exome

AF:

0.0106

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

Gnomad4 AFR exome

AF:

0.000688

Gnomad4 AMR exome

AF:

0.00274

Gnomad4 ASJ exome

AF:

0.000576

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.0117

Gnomad4 FIN exome

AF:

0.00165

Gnomad4 NFE exome

AF:

0.00623

Gnomad4 OTH exome

AF:

0.00493

GnomAD4 genome

AF:

0.00433

AC:

659

AN:

152356

Hom.:

Cov.:

AF XY:

0.00438

AC XY:

326

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.00103

Gnomad4 AMR

AF:

0.00751

Gnomad4 ASJ

AF:

0.000865

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0114

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00607

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00551

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:11

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Uncertain:1Benign:5

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -

not specified

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 23, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	NTRK1: PM5, BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 07, 2016	- -

NTRK1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.066

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.25

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Uncertain

0.57

.;.;D;T

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.73

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.82

T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.59

.;.;N;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.34

Sift

Benign

0.23

T;T;T;T

Sift4G

Benign

0.45

T;T;T;T

Polyphen

0.0050, 0.87

.;B;P;.

Vest4

0.28

MVP

0.79

MPC

0.30

ClinPred

0.0073

GERP RS

4.1

Varity_R

0.24

gMVP

0.65

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over