rs150271893

Positions:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_002529.4(NTRK1):c.482G>A(p.Arg161His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000494 in 1,613,766 control chromosomes in the GnomAD database, with no homozygous occurrence. 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).

Frequency

Genomes: 𝑓 0.00031 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00051 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:2

Conservation

PhyloP100: 0.406

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14326906).

BP6

Variant 1-156868157-G-A is Benign according to our data. Variant chr1-156868157-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 378306.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4}. Variant chr1-156868157-G-A is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NTRK1	NM_002529.4 linkuse as main transcript	c.482G>A	p.Arg161His	missense_variant	5/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 linkuse as main transcript	c.482G>A	p.Arg161His	missense_variant	5/16		NP_001012331.1
NTRK1	NM_001007792.1 linkuse as main transcript	c.392G>A	p.Arg131His	missense_variant	6/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.482G>A	p.Arg161His	missense_variant	5/17	1	NM_002529.4	ENSP00000431418	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.000309

AC:

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000723

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.000603

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000339

AC:

AN:

250506

Hom.:

AF XY:

0.000324

AC XY:

AN XY:

135634

show subpopulations

Gnomad AFR exome

AF:

0.0000619

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000715

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000514

AC:

751

AN:

1461514

Hom.:

Cov.:

AF XY:

0.000477

AC XY:

347

AN XY:

727090

show subpopulations

Gnomad4 AFR exome

AF:

0.000149

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.0000566

Gnomad4 NFE exome

AF:

0.000643

Gnomad4 OTH exome

AF:

0.000315

GnomAD4 genome

AF:

0.000309

AC:

AN:

152252

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74380

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000603

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000773

Hom.:

Bravo

AF:

0.000446

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000698

AC:

ExAC

AF:

0.000305

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000356

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	May 28, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 26, 2023	In silico analysis supports that this missense variant does not alter protein structure/function; Reported in patients with neuroblastoma (Lipska et al., 2009); This variant is associated with the following publications: (PMID: 20003389) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	- -

Hereditary insensitivity to pain with anhidrosis

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

Hereditary cancer

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Mendelics

Jan 23, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.17

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

.;.;T;T

Eigen

Benign

0.076

Eigen_PC

Benign

0.039

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.85

D;D;T;D

M_CAP

Benign

0.025

MetaRNN

Benign

0.14

T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Benign

1.8

.;L;L;.

MutationTaster

Benign

0.63

D;D;D;D

PrimateAI

Benign

0.33

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Uncertain

0.33

Sift

Benign

0.11

T;T;T;T

Sift4G

Benign

0.17

T;T;T;T

Polyphen

0.99, 1.0

.;D;D;.

Vest4

0.33

MVP

0.97

MPC

0.30

ClinPred

0.11

GERP RS

0.77

Varity_R

0.11

gMVP

0.42

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