Variant rs137994522 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002529.4(NTRK1):c.940C>A(p.Arg314Ser) 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 1,460,384 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R314C) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. 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

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23169002).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NTRK1	NM_002529.4 linkuse as main transcript	c.940C>A	p.Arg314Ser	missense_variant	8/17	ENST00000524377.7
NTRK1	NM_001012331.2 linkuse as main transcript	c.940C>A	p.Arg314Ser	missense_variant	8/16
NTRK1	NM_001007792.1 linkuse as main transcript	c.850C>A	p.Arg284Ser	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>A	p.Arg314Ser	missense_variant	8/17	1	NM_002529.4	P4	P04629-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460384

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726388

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.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

.;.;T;T

Eigen

Benign

-0.18

Eigen_PC

Benign

-0.031

FATHMM_MKL

Benign

0.26

LIST_S2

Benign

0.81

T;T;T;T

M_CAP

Benign

0.0044

MetaRNN

Benign

0.23

T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

.;L;L;.

MutationTaster

Benign

0.54

D;D;D;N

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.3

N;N;N;N

REVEL

Benign

0.083

Sift

Benign

0.32

T;T;T;T

Sift4G

Benign

0.86

T;T;T;T

Polyphen

0.065, 0.013

.;B;B;.

Vest4

0.30

MutPred

0.47

.;Loss of catalytic residue at R314 (P = 0.0497);Loss of catalytic residue at R314 (P = 0.0497);Loss of catalytic residue at R314 (P = 0.0497);

MVP

0.63

MPC

0.45

ClinPred

0.38

GERP RS

5.2

Varity_R

0.40

gMVP

0.84

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over