Genetic Variant NTRK1:p.Arg214Leu (chr1-156868571-G-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_002529.4(NTRK1):c.641G>T(p.Arg214Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,402,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 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. R214W) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.168

Publications

0 publications found

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 Gene-Disease associations (from GenCC):

hereditary sensory and autonomic neuropathy type 4
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
familial medullary thyroid carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

NTRK1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 10 uncertain in NM_002529.4

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.20162782).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NTRK1	NM_002529.4 link	c.641G>T	p.Arg214Leu	missense_variant	Exon 6 of 17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 link	c.641G>T	p.Arg214Leu	missense_variant	Exon 6 of 16		NP_001012331.1
NTRK1	NM_001007792.1 link	c.551G>T	p.Arg184Leu	missense_variant	Exon 7 of 17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.641G>T	p.Arg214Leu	missense_variant	Exon 6 of 17	1	NM_002529.4	ENSP00000431418.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000143

AC:

AN:

1402090

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

691830

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31766

American (AMR)

AF:

0.00

AC:

AN:

36152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25194

East Asian (EAS)

AF:

0.00

AC:

AN:

36004

South Asian (SAS)

AF:

0.00

AC:

AN:

79406

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49336

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5568

European-Non Finnish (NFE)

AF:

0.00000185

AC:

AN:

1080540

Other (OTH)

AF:

0.00

AC:

AN:

58124

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.22

DEOGEN2

Benign

0.0

.;.;T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.26

T;T;T;T

M_CAP

Benign

0.0040

MetaRNN

Benign

0.20

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.0

.;L;L;.

PhyloP100

0.17

PrimateAI

Benign

0.21

PROVEAN

Benign

-0.48

N;N;N;N

REVEL

Benign

0.042

Sift

Benign

0.62

T;T;T;T

Sift4G

Benign

0.64

T;T;T;T

Vest4

0.31

ClinPred

0.079

GERP RS

-0.78

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.61

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over