rs543320028

Positions:

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002529.4(NTRK1):c.253C>A(p.Arg85Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict 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. R85C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:6

Conservation

PhyloP100: -0.774

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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.045861065).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.253C>A	p.Arg85Ser	missense_variant	2/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.253C>A	p.Arg85Ser	missense_variant	2/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.163C>A	p.Arg55Ser	missense_variant	3/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.253C>A	p.Arg85Ser	missense_variant	2/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.0000460

AC:

AN:

152074

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251346

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135866

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000821

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000447

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:

0.00000360

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.0000460

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74404

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000869

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Mar 05, 2020	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Feb 13, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 23, 2022	This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 85 of the NTRK1 protein (p.Arg85Ser). This variant is present in population databases (rs543320028, gnomAD 0.003%). This missense change has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 10330344, 32707409). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 584593). 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) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. Experimental studies have shown that this missense change does not substantially affect NTRK1 function (PMID: 11719521). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Aug 19, 2021

Variant summary: NTRK1 c.253C>A (p.Arg85Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251346 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.253C>A has been reported in the literature to co-occur in-cis with a pathogenic variant (c.429-1G>C) in a homozygous individual affected with Hereditary Insensitivity To Pain With Anhidrosis (Mardy_1999). It has also been reported to segregate with disease in two compound heterozygous siblings that had inherited each of their variants from their carrier parents (Hartono_2020). These reports do not allow any unequivocal conclusions about significance of the variant. Experimental evidence evaluating an impact on protein function through utilization of a combination of biochemical and biological assays, demonstrated the variant to have similar activity to wild-type (Mardy_2001, Miranda_2002). A ClinVar submitter (evaluation after 2014) cites the variant as likely pathogenic, while another ClinVar submitter (evaluation after 2014) cites it as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Charcot-Marie-Tooth disease

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Inherited Neuropathy Consortium

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 31, 2020

The p.R85S variant (also known as c.253C>A), located in coding exon 2 of the NTRK1 gene, results from a C to A substitution at nucleotide position 253. The arginine at codon 85 is replaced by serine, an amino acid with dissimilar properties. This variant was detected in the homozygous state in an individual with congenital insensitivity to pain with anhidrosis (CIPA) who also had another homozygous variant in NTRK1 (c.429-1G>C) (Mardy S et al. Am J Hum Genet, 1999 Jun;64:1570-9). In addition, the p.R85S variant was found to segregate with CIPA in two affected siblings with CIPA, who were both compound heterozygotes for NTRK1 p.R85S (c.253C>A) and p.R692C (c.2074C>T) (Hartono F et al. Int J Surg Case Rep, 2020 Jul;73:213-217). Protein functional studies suggest that this alteration does not impair normal processing or autophosphorylation of NTRK1 (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 poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.012

BayesDel_noAF

Benign

-0.17

CADD

Benign

0.21

DANN

Benign

0.76

DEOGEN2

Benign

0.30

.;.;T;T

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.29

T;T;T;T

M_CAP

Benign

0.073

MetaRNN

Benign

0.046

T;T;T;T

MetaSVM

Benign

-0.78

MutationAssessor

Benign

-0.030

.;N;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Benign

0.26

PROVEAN

Benign

0.21

N;N;N;N

REVEL

Uncertain

0.52

Sift

Benign

0.73

T;T;T;T

Sift4G

Benign

0.72

T;T;T;T

Polyphen

0.0

.;B;B;.

Vest4

0.43

MutPred

0.35

.;Gain of disorder (P = 0.0839);Gain of disorder (P = 0.0839);Gain of disorder (P = 0.0839);

MVP

0.65

MPC

0.27

ClinPred

0.028

GERP RS

-6.4

Varity_R

0.25

gMVP

0.39

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.20

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.20

Position offset: 34

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