rs121964870

Positions:

• chr1-156876526-A-G
• chr1-156876526-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_002529.4(NTRK1):​c.1759A>G​(p.Met587Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.48

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 Likely_pathogenic. Variant got 7 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 1-156876526-A-G is Pathogenic according to our data. Variant chr1-156876526-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 12312.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-156876526-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.1759A>G	p.Met587Val	missense_variant	14/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.1741A>G	p.Met581Val	missense_variant	13/16
NTRK1	NM_001007792.1	c.1651A>G	p.Met551Val	missense_variant	14/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.1759A>G	p.Met587Val	missense_variant	14/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Oct 01, 2002	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	May 16, 2019	For these reasons, this variant has been classified as Pathogenic. This variant has been reported to affect NTRK1 protein function (PMID: 12406349). This variant has been observed to segregate with hereditary sensory and autonomic neuropathy in a family (PMID: 0233776). ClinVar contains an entry for this variant (Variation ID: 12312). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with valine at codon 581 of the NTRK1 protein (p.Met581Val). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and valine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	27
DANN	Uncertain	1.0
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	-0.19	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-3.6	D;D;D;D
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		0.51, 0.99	.;P;D;.
Vest4		0.72
MutPred		0.61		.;.;Loss of phosphorylation at Y591 (P = 0.2187);.;
MVP		0.90
MPC		0.88
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.92
gMVP		0.67

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

Other links and lift over

dbSNP: rs121964870; hg19: chr1-156846318;