rs766307207

Positions:

• chr1-156861119-T-C

Variant summary

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

The NM_002529.4(NTRK1):​c.185T>C​(p.Leu62Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000512 in 1,582,254 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000046 (1 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 2.48

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.185T>C	p.Leu62Pro	missense_variant	1/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.185T>C	p.Leu62Pro	missense_variant	1/16		NP_001012331.1
NTRK1	NM_001007792.1	c.123-3235T>C		intron_variant			NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.185T>C	p.Leu62Pro	missense_variant	1/17	1	NM_002529.4	ENSP00000431418	P4

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000625 AC: 12 AN: 191878 Hom.: 0 AF XY: 0.0000565 AC XY: 6 AN XY: 106278

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000638

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: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000462 AC: 66 AN: 1429934 Hom.: 1 Cov.: 32 AF XY: 0.0000493 AC XY: 35 AN XY: 709576

Gnomad4 AFR exome AF: 0.0000302

Gnomad4 AMR exome AF: 0.0000942

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000237

Gnomad4 NFE exome AF: 0.0000455

Gnomad4 OTH exome AF: 0.0000844

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74494

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000101 Hom.: 0

Bravo AF: 0.000185

ExAC AF: 0.0000760 AC: 9

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Uncertain:4

Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 62 of the NTRK1 protein (p.Leu62Pro). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. ClinVar contains an entry for this variant (Variation ID: 573468). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt NTRK1 protein function. 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, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 17, 2021	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 11, 2019	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 20, 2018	In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 22, 2023

The c.185T>C (p.L62P) alteration is located in exon 1 (coding exon 1) of the NTRK1 gene. This alteration results from a T to C substitution at nucleotide position 185, causing the leucine (L) at amino acid position 62 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.30
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;T;T
Eigen	Benign	0.089
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.65	T;T;T
M_CAP	Pathogenic	0.88	D
MetaRNN	Uncertain	0.56	D;D;D
MetaSVM	Uncertain	0.69	D
MutationAssessor	Benign	1.8	L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Pathogenic	0.69
Sift	Uncertain	0.0020	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		0.42	B;D;.
Vest4		0.47
MVP		0.97
MPC		0.76
ClinPred		0.16	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.71

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: rs766307207; hg19: chr1-156830911;