chr1-156873722-C-T

Position:

chr1-156873722-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM1BP4_Strong

The NM_002529.4(NTRK1):c.940C>T(p.Arg314Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000226 in 1,612,666 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts 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. R314H) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 1 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:1

Conservation

PhyloP100: 1.38

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 -2 ACMG points.

PM1

In a domain Ig-like C2-type 2 (size 66) in uniprot entity NTRK1_HUMAN there are 4 pathogenic changes around while only 0 benign (100%) in NM_002529.4

BP4

Computational evidence support a benign effect (MetaRNN=0.013421059).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.940C>T	p.Arg314Cys	missense_variant	8/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.940C>T	p.Arg314Cys	missense_variant	8/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.850C>T	p.Arg284Cys	missense_variant	9/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.940C>T	p.Arg314Cys	missense_variant	8/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.00118

AC:

180

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00405

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000271

AC:

AN:

247302

Hom.:

AF XY:

0.000261

AC XY:

AN XY:

134086

show subpopulations

Gnomad AFR exome

AF:

0.00318

Gnomad AMR exome

AF:

0.0000583

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000331

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.000126

AC:

184

AN:

1460382

Hom.:

Cov.:

AF XY:

0.000127

AC XY:

AN XY:

726386

show subpopulations

Gnomad4 AFR exome

AF:

0.00386

Gnomad4 AMR exome

AF:

0.0000672

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000291

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000720

Gnomad4 OTH exome

AF:

0.000299

GnomAD4 genome

AF:

0.00118

AC:

180

AN:

152284

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00407

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000828

Hom.:

Bravo

AF:

0.00120

ESP6500AA

AF:

0.00522

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000428

AC:

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2015	The R314C variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The NHLBI Exome Sequencing Project and the 1000 Genomes Project reports R314C was observed in 0.5-2.5% alleles from individuals of African background, indicating it may be a rare (benign) variant in this population. The R314C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. However, this substitution occurs at a position that is not conserved, and in silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

Familial medullary thyroid carcinoma

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mendelics

Jul 02, 2018

- -

Hereditary insensitivity to pain with anhidrosis

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.73

.;.;D;T

Eigen

Uncertain

0.39

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.30

LIST_S2

Uncertain

0.95

D;D;D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.013

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Benign

0.45

PROVEAN

Uncertain

-3.5

D;D;D;D

REVEL

Benign

0.19

Sift

Uncertain

0.014

D;D;D;D

Sift4G

Uncertain

0.043

D;T;T;T

Polyphen

1.0, 0.99

.;D;D;.

Vest4

0.60

MVP

0.59

MPC

0.91

ClinPred

0.063

GERP RS

5.2

Varity_R

0.24

gMVP

0.89

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