rs35669708

chr1-156881590-G-Achr1-156881590-G-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 4P and 9B. PM1 PM5 BP4_Strong BP6 BS2

The NM_002529.4(NTRK1):c.2339G>A(p.Arg780Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00569 in 1,611,386 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R780P) has been classified as Pathogenic.

• Frequency:
  • Genomes: 𝑓 0.0043 (7 hom., cov: 33)
  • Exomes 𝑓: 0.0058 (36 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:11
• Conservation: PhyloP100: 0.472

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_benign. Variant got -5 ACMG points.

• PM1: In a domain Protein kinase (size 271) in uniprot entity NTRK1_HUMAN there are 69 pathogenic changes around while only 22 benign (76%) in NM_002529.4
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr1-156881590-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 12303.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.012337536).
• BP6: Variant 1-156881590-G-A is Benign according to our data. Variant chr1-156881590-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235534.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Likely_benign=5, Uncertain_significance=1}. Variant chr1-156881590-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.2339G>A	p.Arg780Gln	missense_variant	17/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.2321G>A	p.Arg774Gln	missense_variant	16/16
NTRK1	NM_001007792.1	c.2231G>A	p.Arg744Gln	missense_variant	17/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.2339G>A	p.Arg780Gln	missense_variant	17/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.00434 AC: 660 AN: 152238 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.00104

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00752

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.00132

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00607

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00480 AC: 1166 AN: 243110 Hom.: 10 AF XY: 0.00537 AC XY: 710 AN XY: 132246

Gnomad AFR exome AF: 0.000716

Gnomad AMR exome AF: 0.00279

Gnomad ASJ exome AF: 0.000304

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0106

Gnomad FIN exome AF: 0.00103

Gnomad NFE exome AF: 0.00635

Gnomad OTH exome AF: 0.00372

GnomAD4 exome AF: 0.00583 AC: 8513 AN: 1459030 Hom.: 36 Cov.: 31 AF XY: 0.00613 AC XY: 4449 AN XY: 725604

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00274

Gnomad4 ASJ exome AF: 0.000576

Gnomad4 EAS exome AF: 0.0000757

Gnomad4 SAS exome AF: 0.0117

Gnomad4 FIN exome AF: 0.00165

Gnomad4 NFE exome AF: 0.00623

Gnomad4 OTH exome AF: 0.00493

GnomAD4 genome AF: 0.00433 AC: 659 AN: 152356 Hom.: 7 Cov.: 33 AF XY: 0.00438 AC XY: 326 AN XY: 74496

Gnomad4 AFR AF: 0.00103

Gnomad4 AMR AF: 0.00751

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0114

Gnomad4 FIN AF: 0.00132

Gnomad4 NFE AF: 0.00607

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00551 Hom.: 7

Bravo AF: 0.00383

TwinsUK AF: 0.00755 AC: 28

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00465 AC: 40

ExAC AF: 0.00489 AC: 593

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:11

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Uncertain:1 Benign:5

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	May 18, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 07, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	NTRK1: PM5, BP4, BS1, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 02, 2018	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 18, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

NTRK1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Benign	18
Dann	Benign	0.95
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.82	T;T;T;T
MetaRNN	Benign	0.012	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.3	N;N;N;N
REVEL	Uncertain	0.34
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.45	T;T;T;T
Polyphen		0.0050, 0.87	.;B;P;.
Vest4		0.28
MVP		0.79
MPC		0.30
ClinPred		0.0073	T
GERP RS		4.1
Varity_R		0.24
gMVP		0.65

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: rs35669708; hg19: chr1-156851382; COSMIC: COSV62324745;