Variant 1-156881590-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3PP5

The NM_002529.4(NTRK1):c.2339G>C(p.Arg780Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,459,036 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 Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R780Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 0.472

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_pathogenic. Variant got 6 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

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.823

PP5

Variant 1-156881590-G-C is Pathogenic according to our data. Variant chr1-156881590-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12303.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr1-156881590-G-C is described in Lovd as [Pathogenic]. Variant chr1-156881590-G-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.2339G>C	p.Arg780Pro	missense_variant	17/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.2321G>C	p.Arg774Pro	missense_variant	16/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.2231G>C	p.Arg744Pro	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.2339G>C	p.Arg780Pro	missense_variant	17/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000411

AC:

AN:

243110

Hom.:

AF XY:

0.00000756

AC XY:

AN XY:

132246

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000912

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1459036

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

725610

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:

0.00000180

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.69

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.10

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.27

LIST_S2

Uncertain

0.93

D;D;D;D

M_CAP

Benign

0.063

MetaRNN

Pathogenic

0.82

D;D;D;D

MetaSVM

Benign

-0.35

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.49

PROVEAN

Uncertain

-2.5

D;D;D;D

REVEL

Uncertain

0.56

Sift

Benign

0.16

T;T;T;T

Sift4G

Benign

0.28

T;T;T;T

Polyphen

0.70, 0.98

.;P;D;.

Vest4

0.81

MutPred

0.63

.;.;Loss of MoRF binding (P = 0.006);.;

MVP

0.93

MPC

0.97

ClinPred

0.80

GERP RS

4.1

Varity_R

0.95

gMVP

0.92

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