1-156879126-C-T

Position:

chr1-156879126-C-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.1810C>T(p.His604Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0533 in 1,613,612 control chromosomes in the GnomAD database, including 2,658 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. H604H) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.038 ( 147 hom., cov: 31)

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: 7.83

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 Benign. Variant got -18 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

BP4

Computational evidence support a benign effect (MetaRNN=0.007919282).

BP6

Variant 1-156879126-C-T is Benign according to our data. Variant chr1-156879126-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 37077.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156879126-C-T is described in Lovd as [Benign]. Variant chr1-156879126-C-T is described in Lovd as [Likely_benign]. Variant chr1-156879126-C-T is described in Lovd as [Likely_pathogenic].

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0557 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4 linkuse as main transcript	c.1810C>T	p.His604Tyr	missense_variant	15/17	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 linkuse as main transcript	c.1792C>T	p.His598Tyr	missense_variant	14/16		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 linkuse as main transcript	c.1702C>T	p.His568Tyr	missense_variant	15/17		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.1810C>T	p.His604Tyr	missense_variant	15/17	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.0376

AC:

5720

AN:

152056

Hom.:

147

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0105

Gnomad AMI

AF:

0.0428

Gnomad AMR

AF:

0.0310

Gnomad ASJ

AF:

0.0687

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0564

Gnomad FIN

AF:

0.0263

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0572

Gnomad OTH

AF:

0.0402

GnomAD3 exomes

AF:

0.0416

AC:

10359

AN:

248732

Hom.:

292

AF XY:

0.0446

AC XY:

6006

AN XY:

134770

show subpopulations

Gnomad AFR exome

AF:

0.00851

Gnomad AMR exome

AF:

0.0236

Gnomad ASJ exome

AF:

0.0636

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0556

Gnomad FIN exome

AF:

0.0269

Gnomad NFE exome

AF:

0.0554

Gnomad OTH exome

AF:

0.0505

GnomAD4 exome

AF:

0.0549

AC:

80241

AN:

1461438

Hom.:

2511

Cov.:

AF XY:

0.0553

AC XY:

40229

AN XY:

727022

show subpopulations

Gnomad4 AFR exome

AF:

0.00810

Gnomad4 AMR exome

AF:

0.0245

Gnomad4 ASJ exome

AF:

0.0647

Gnomad4 EAS exome

AF:

0.000227

Gnomad4 SAS exome

AF:

0.0571

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0604

Gnomad4 OTH exome

AF:

0.0532

GnomAD4 genome

AF:

0.0376

AC:

5717

AN:

152174

Hom.:

147

Cov.:

AF XY:

0.0351

AC XY:

2613

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.0104

Gnomad4 AMR

AF:

0.0309

Gnomad4 ASJ

AF:

0.0687

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.0562

Gnomad4 FIN

AF:

0.0263

Gnomad4 NFE

AF:

0.0572

Gnomad4 OTH

AF:

0.0398

Alfa

AF:

0.0528

Hom.:

198

Bravo

AF:

0.0366

TwinsUK

AF:

0.0556

AC:

206

ALSPAC

AF:

0.0584

AC:

225

ESP6500AA

AF:

0.0118

AC:

ESP6500EA

AF:

0.0605

AC:

520

ExAC

AF:

0.0422

AC:

5125

Asia WGS

AF:

0.0220

AC:

AN:

3478

EpiCase

AF:

0.0534

EpiControl

AF:

0.0555

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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
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, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
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	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

not provided

Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	This variant is associated with the following publications: (PMID: 27884173, 10330344, 21228398, 20981092, 19435634, 11719521, 18780967, 11159935, 22995991, 20003389) -
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

0.33

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.83

.;.;D;D

Eigen

Uncertain

0.60

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

D;D;D;D

MetaRNN

Benign

0.0079

T;T;T;T

MetaSVM

Uncertain

0.18

MutationAssessor

Benign

1.3

.;.;L;.

PrimateAI

Pathogenic

0.80

PROVEAN

Pathogenic

-5.3

D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;D

Polyphen

0.99, 0.99

.;D;D;.

Vest4

0.61

MPC

0.89

ClinPred

0.018

GERP RS

4.4

Varity_R

0.96

gMVP

0.68

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