chr1-156875555-A-T

Position:

• chr1-156875555-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_002529.4(NTRK1):​c.1390A>T​(p.Met464Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.735

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]

ACMG classification

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=0.15594104).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.1390A>T	p.Met464Leu	missense_variant	12/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.1372A>T	p.Met458Leu	missense_variant	11/16		NP_001012331.1
NTRK1	NM_001007792.1	c.1282A>T	p.Met428Leu	missense_variant	12/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.1390A>T	p.Met464Leu	missense_variant	12/17	1	NM_002529.4	ENSP00000431418	P4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 24, 2018

This sequence change replaces methionine with leucine at codon 458 of the NTRK1 protein (p.Met458Leu). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with NTRK1-related disease. 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	20
DANN	Benign	0.81
DEOGEN2	Benign	0.39	.;.;T;T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.82	T;T;T;T
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.16	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.0	.;.;M;.
MutationTaster	Benign	0.96	D;D;D;D
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.31
Sift	Benign	0.73	T;T;T;T
Sift4G	Benign	0.54	T;T;T;T
Polyphen		0.0	.;B;B;.
Vest4		0.36
MutPred		0.41		.;.;Loss of catalytic residue at M464 (P = 0.0722);.;
MVP		0.70
MPC		0.23
ClinPred		0.48	T
GERP RS		4.5
Varity_R		0.38
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs765177801; hg19: chr1-156845347;