1-156864394-C-T

Position:

• chr1-156864394-C-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.253C>T​(p.Arg85Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000026 in 1,461,870 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. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000026 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: -0.774

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=0.14804366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NTRK1	NM_002529.4	c.253C>T	p.Arg85Cys	missense_variant	2/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2	c.253C>T	p.Arg85Cys	missense_variant	2/16		NP_001012331.1
NTRK1	NM_001007792.1	c.163C>T	p.Arg55Cys	missense_variant	3/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7	c.253C>T	p.Arg85Cys	missense_variant	2/17	1	NM_002529.4	ENSP00000431418	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000119 AC: 3 AN: 251346 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000260 AC: 38 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000234 AC XY: 17 AN XY: 727234

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000297

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000340

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Uncertain:3

Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 10, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 01, 2021	This sequence change replaces arginine with cysteine at codon 85 of the NTRK1 protein (p.Arg85Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs543320028, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with NTRK1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). 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	Genome-Nilou Lab	Apr 11, 2023	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.253C>T (p.R85C) alteration is located in exon 2 (coding exon 2) of the NTRK1 gene. This alteration results from a C to T substitution at nucleotide position 253, causing the arginine (R) at amino acid position 85 to be replaced by a cysteine (C). 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	0.13
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	14
DANN	Benign	0.93
DEOGEN2	Uncertain	0.47	.;.;T;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.058	N
LIST_S2	Benign	0.73	T;T;T;T
M_CAP	Uncertain	0.097	D
MetaRNN	Benign	0.15	T;T;T;T
MetaSVM	Benign	-0.37	T
MutationAssessor	Uncertain	2.1	.;M;M;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.27
Sift	Benign	0.054	T;T;T;T
Sift4G	Uncertain	0.048	D;D;D;D
Polyphen		0.55, 0.18	.;P;B;.
Vest4		0.22
MutPred		0.42		.;Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);Loss of disorder (P = 0.0183);
MVP		0.76
MPC		0.38
ClinPred		0.13	T
GERP RS		-6.4
Varity_R		0.094
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs543320028; hg19: chr1-156834186; COSMIC: COSV62327953;