rs6339

Positions:

chr1-156879154-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_002529.4(NTRK1):c.1838G>T(p.Gly613Val) variant causes a missense change. The variant allele was found at a frequency of 0.0533 in 1,613,774 control chromosomes in the GnomAD database, including 2,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.038 ( 146 hom., cov: 32)

Exomes 𝑓: 0.055 ( 2511 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:15O:1

Conservation

PhyloP100: 3.65

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 Benign. Variant got -18 ACMG points.

PM1

In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 42 pathogenic changes around while only 5 benign (89%) in NM_002529.4

BP4

Computational evidence support a benign effect (MetaRNN=0.0029589236).

BP6

Variant 1-156879154-G-T is Benign according to our data. Variant chr1-156879154-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 12308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156879154-G-T is described in Lovd as [Benign]. Variant chr1-156879154-G-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NTRK1	NM_002529.4 linkuse as main transcript	c.1838G>T	p.Gly613Val	missense_variant	15/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 linkuse as main transcript	c.1820G>T	p.Gly607Val	missense_variant	14/16		NP_001012331.1
NTRK1	NM_001007792.1 linkuse as main transcript	c.1730G>T	p.Gly577Val	missense_variant	15/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.1838G>T	p.Gly613Val	missense_variant	15/17	1	NM_002529.4	ENSP00000431418	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.0377

AC:

5726

AN:

152068

Hom.:

146

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0104

Gnomad AMI

AF:

0.0429

Gnomad AMR

AF:

0.0309

Gnomad ASJ

AF:

0.0686

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0570

Gnomad FIN

AF:

0.0262

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0573

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0417

AC:

10381

AN:

249090

Hom.:

291

AF XY:

0.0446

AC XY:

6013

AN XY:

134858

show subpopulations

Gnomad AFR exome

AF:

0.00860

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0635

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0552

Gnomad FIN exome

AF:

0.0272

Gnomad NFE exome

AF:

0.0555

Gnomad OTH exome

AF:

0.0502

GnomAD4 exome

AF:

0.0550

AC:

80333

AN:

1461588

Hom.:

2511

Cov.:

AF XY:

0.0554

AC XY:

40280

AN XY:

727104

show subpopulations

Gnomad4 AFR exome

AF:

0.00810

Gnomad4 AMR exome

AF:

0.0244

Gnomad4 ASJ exome

AF:

0.0647

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0569

Gnomad4 FIN exome

AF:

0.0300

Gnomad4 NFE exome

AF:

0.0605

Gnomad4 OTH exome

AF:

0.0532

GnomAD4 genome

AF:

0.0376

AC:

5723

AN:

152186

Hom.:

146

Cov.:

AF XY:

0.0352

AC XY:

2619

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0309

Gnomad4 ASJ

AF:

0.0686

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0568

Gnomad4 FIN

AF:

0.0262

Gnomad4 NFE

AF:

0.0573

Gnomad4 OTH

AF:

0.0397

Alfa

AF:

0.0522

Hom.:

395

Bravo

AF:

0.0366

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0586

AC:

226

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0603

AC:

519

ExAC

AF:

0.0421

AC:

5116

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0536

EpiControl

AF:

0.0556

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:15Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Benign:6Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -

not specified

Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2014	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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial medullary thyroid carcinoma

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.099

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.13

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.74

.;.;D;D

Eigen

Benign

-0.019

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.94

LIST_S2

Benign

0.81

T;T;T;T

MetaRNN

Benign

0.0030

T;T;T;T

MetaSVM

Benign

-0.58

MutationAssessor

Benign

1.4

.;.;L;.

MutationTaster

Benign

1.0

A;A;A;A

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-2.7

D;D;D;D

REVEL

Uncertain

0.34

Sift

Uncertain

0.023

D;D;D;D

Sift4G

Benign

0.11

T;T;T;T

Polyphen

0.13, 0.38

.;B;B;.

Vest4

0.20

MPC

0.48

ClinPred

0.018

GERP RS

3.4

Varity_R

0.34

gMVP

0.72

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