rs747711259

Positions:

chr1-156868568-T-C

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong

The NM_002529.4(NTRK1):c.638T>C(p.Leu213Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000122 in 1,554,906 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. L213L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5U:1

Conservation

PhyloP100: 3.79

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 Pathogenic. Variant got 16 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 10 uncertain in NM_002529.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.969

PP5

Variant 1-156868568-T-C is Pathogenic according to our data. Variant chr1-156868568-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 526734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156868568-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.638T>C	p.Leu213Pro	missense_variant	6/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.638T>C	p.Leu213Pro	missense_variant	6/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.548T>C	p.Leu183Pro	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.638T>C	p.Leu213Pro	missense_variant	6/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152050

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000121

AC:

AN:

1402856

Hom.:

Cov.:

AF XY:

0.0000159

AC XY:

AN XY:

692302

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000157

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152050

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000473

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000922

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5Uncertain:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 18, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 213 of the NTRK1 protein (p.Leu213Pro). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with autosomal recessive congenital insensitivity to pain with anhidrosis (PMID: 10330344, 12949319). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 526734). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on NTRK1 protein function. Experimental studies have shown that this missense change affects NTRK1 function (PMID: 11159935, 11719521, 27551041). For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 25, 2021	- -

Inborn genetic diseases

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2021

The p.L213P variant (also known as c.638T>C), located in coding exon 6 of the NTRK1 gene, results from a T to C substitution at nucleotide position 638. The leucine at codon 213 is replaced by proline, an amino acid with similar properties. This alteration was detected in trans with truncating mutations in NTRK1 in two unrelated individuals (Mardy S et al. Am J Hum Genet, 1999 Jun;64:1570-9; Bonkowsky JL et al. Pediatrics, 2003 Sep;112:e237-41). Functional studies indicate that this alteration results in abnormal localization and loss of activation of the NTRK1 protein (Franco ML et al. J Biol Chem, 2016 Oct;291:21363-21374; Mardy S et al. Hum Mol Genet, 2001 Feb;10:179-88; Miranda C et al. J Biol Chem, 2002 Feb;277:6455-62). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;.;D;T

Eigen

Benign

0.15

Eigen_PC

Benign

-0.023

FATHMM_MKL

Benign

0.49

LIST_S2

Benign

0.78

T;T;T;T

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.97

D;D;D;D

MetaSVM

Benign

-0.88

MutationAssessor

Uncertain

2.6

.;M;M;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.51

PROVEAN

Uncertain

-4.2

D;D;D;D

REVEL

Uncertain

0.48

Sift

Uncertain

0.0020

D;D;D;D

Sift4G

Uncertain

0.0050

D;D;D;D

Polyphen

1.0

.;D;D;.

Vest4

0.96

MutPred

0.76

.;Loss of stability (P = 0.0467);Loss of stability (P = 0.0467);Loss of stability (P = 0.0467);

MVP

0.93

MPC

1.1

ClinPred

0.96

GERP RS

3.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.93

gMVP

0.98

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