rs200815412

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_002529.4(NTRK1):c.157G>A(p.Asp53Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000489 in 1,431,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D53H) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:2

Conservation

PhyloP100: -0.245

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07954708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.157G>A	p.Asp53Asn	missense_variant	1/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.157G>A	p.Asp53Asn	missense_variant	1/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.123-3263G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.157G>A	p.Asp53Asn	missense_variant	1/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000508

AC:

AN:

196792

Hom.:

AF XY:

0.00

AC XY:

AN XY:

108960

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:

0.0000119

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000489

AC:

AN:

1431902

Hom.:

Cov.:

AF XY:

0.00000563

AC XY:

AN XY:

710846

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:

0.00000636

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Sep 01, 2021	This sequence change replaces aspartic acid with asparagine at codon 53 of the NTRK1 protein (p.Asp53Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. 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. -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Mar 07, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.33

.;T;T

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.78

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.76

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.080

T;T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

-1.0

N;N;.

MutationTaster

Benign

1.0

N;N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.47

N;N;N

REVEL

Benign

0.20

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.22

T;T;T

Polyphen

0.0

B;B;.

Vest4

0.067

MutPred

0.42

Loss of catalytic residue at D53 (P = 0.0292);Loss of catalytic residue at D53 (P = 0.0292);Loss of catalytic residue at D53 (P = 0.0292);

MVP

0.76

MPC

0.24

ClinPred

0.052

GERP RS

0.76

Varity_R

0.19

gMVP

0.23

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