rs754452975

chr1-156880009-G-Achr1-156880009-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_002529.4(NTRK1):c.2057G>A(p.Arg686His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000608 in 1,612,744 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R686C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:8
• Conservation: PhyloP100: 0.409

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 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002529.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32946616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.2057G>A	p.Arg686His	missense_variant	16/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.2039G>A	p.Arg680His	missense_variant	15/16
NTRK1	NM_001007792.1	c.1949G>A	p.Arg650His	missense_variant	16/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.2057G>A	p.Arg686His	missense_variant	16/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.0000724 AC: 11 AN: 152000 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 249992 Hom.: 0 AF XY: 0.0000369 AC XY: 5 AN XY: 135432

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000596 AC: 87 AN: 1460744 Hom.: 0 Cov.: 32 AF XY: 0.0000495 AC XY: 36 AN XY: 726748

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000746

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000724 AC: 11 AN: 152000 Hom.: 0 Cov.: 31 AF XY: 0.0000808 AC XY: 6 AN XY: 74250

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000113 Hom.: 0

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000165 AC: 2

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:8

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	Illumina Laboratory Services, Illumina	Apr 28, 2017	The NTRK1 c.2039G>A (p.Arg680His) missense variant (also referred to as c.2057G>A, p.Arg686His), has been reported in one study in which it is found in a compound heterozygous state with a second missense variant in one individual with congenital insensitivity to pain with anhidrosis (Gao et al. 2013). The variant was also found in a heterozygous state in one of the unaffected parents. The p.Arg680His variant was absent from 100 controls and is reported at a frequency of 0.00006 in the South Asian population, however this is based on one allele so the variant is presumed to be rare. The evidence for this variant is limited. The p.Arg680His variant is therefore classified as a variant of unknown significance but suspicious for pathogenicity for congenital insensitivity to pain with anhidrosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 680 of the NTRK1 protein (p.Arg680His). This variant is present in population databases (rs754452975, gnomAD 0.004%). This missense change has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (PMID: 23799134). This variant is also known as p.Arg686His. ClinVar contains an entry for this variant (Variation ID: 194476). 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 with a negative predictive value of 80%. 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	- -
Uncertain significance, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 03, 2015	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2020	In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 23799134) -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 24, 2021

Variant summary: NTRK1 c.2039G>A (p.Arg680His) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2.4e-05 in 249992 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2039G>A has been reported in the literature in a compound heterozygous individual affected with Hereditary Insensitivity To Pain With Anhidrosis (Gao_2013). This report does not provide unequivocal conclusions about association of the variant with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 17, 2023

The c.2039G>A (p.R680H) alteration is located in exon 15 (coding exon 15) of the NTRK1 gene. This alteration results from a G to A substitution at nucleotide position 2039, causing the arginine (R) at amino acid position 680 to be replaced by a histidine (H). 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	-0.030	T
BayesDel_noAF	Benign	-0.17
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.89	D;D;D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.30	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	1.1	N;N;N;N
REVEL	Uncertain	0.42
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.84, 0.59	.;P;P;.
Vest4		0.42
MutPred		0.61		.;.;Loss of methylation at R686 (P = 0.0222);.;
MVP		0.86
MPC		0.99
ClinPred		0.46	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.36
gMVP		0.66

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

LitVar

Other links and lift over

dbSNP: rs754452975; hg19: chr1-156849801; COSMIC: COSV62325105; COSMIC: COSV62325105;