rs6339

chr1-156879154-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_002529.4(NTRK1):c.1838G>T(p.Gly613Val) variant causes a missense change. The variant allele was found at a frequency of 0.0533 in 1,613,774 control chromosomes in the GnomAD database, including 2,657 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.038 (146 hom., cov: 32)
  • Exomes 𝑓: 0.055 (2511 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:14 O:1
• Conservation: PhyloP100: 3.65

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 Benign. Variant got -18 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
• BP4: Computational evidence support a benign effect (MetaRNN=0.0029589236).
• BP6: Variant 1-156879154-G-T is Benign according to our data. Variant chr1-156879154-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 12308.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156879154-G-T is described in Lovd as [Benign]. Variant chr1-156879154-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0558 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.1838G>T	p.Gly613Val	missense_variant	15/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.1820G>T	p.Gly607Val	missense_variant	14/16
NTRK1	NM_001007792.1	c.1730G>T	p.Gly577Val	missense_variant	15/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.1838G>T	p.Gly613Val	missense_variant	15/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.0377 AC: 5726 AN: 152068 Hom.: 146 Cov.: 32

Gnomad AFR AF: 0.0104

Gnomad AMI AF: 0.0429

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0570

Gnomad FIN AF: 0.0262

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0573

Gnomad OTH AF: 0.0402

GnomAD3 exomes AF: 0.0417 AC: 10381 AN: 249090 Hom.: 291 AF XY: 0.0446 AC XY: 6013 AN XY: 134858

Gnomad AFR exome AF: 0.00860

Gnomad AMR exome AF: 0.0236

Gnomad ASJ exome AF: 0.0635

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0552

Gnomad FIN exome AF: 0.0272

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0502

GnomAD4 exome AF: 0.0550 AC: 80333 AN: 1461588 Hom.: 2511 Cov.: 32 AF XY: 0.0554 AC XY: 40280 AN XY: 727104

Gnomad4 AFR exome AF: 0.00810

Gnomad4 AMR exome AF: 0.0244

Gnomad4 ASJ exome AF: 0.0647

Gnomad4 EAS exome AF: 0.000227

Gnomad4 SAS exome AF: 0.0569

Gnomad4 FIN exome AF: 0.0300

Gnomad4 NFE exome AF: 0.0605

Gnomad4 OTH exome AF: 0.0532

GnomAD4 genome AF: 0.0376 AC: 5723 AN: 152186 Hom.: 146 Cov.: 32 AF XY: 0.0352 AC XY: 2619 AN XY: 74412

Gnomad4 AFR AF: 0.0104

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0568

Gnomad4 FIN AF: 0.0262

Gnomad4 NFE AF: 0.0573

Gnomad4 OTH AF: 0.0397

Alfa AF: 0.0522 Hom.: 395

Bravo AF: 0.0366

TwinsUK AF: 0.0556 AC: 206

ALSPAC AF: 0.0586 AC: 226

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0603 AC: 519

ExAC AF: 0.0421 AC: 5116

Asia WGS AF: 0.0220 AC: 77 AN: 3478

EpiCase AF: 0.0536

EpiControl AF: 0.0556

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:14 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:6 Other:1

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	- -
Likely benign, 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). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Apr 17, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:6

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 23, 2014	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. -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 01, 2017	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 05, 2017	- -

Familial medullary thyroid carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 1999

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.019
Eigen_PC	Benign	0.092
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.81	T;T;T;T
MetaRNN	Benign	0.0030	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-2.7	D;D;D;D
REVEL	Uncertain	0.34
Sift	Uncertain	0.023	D;D;D;D
Sift4G	Benign	0.11	T;T;T;T
Polyphen		0.13, 0.38	.;B;B;.
Vest4		0.20
MPC		0.48
ClinPred		0.018	T
GERP RS		3.4
Varity_R		0.34
gMVP		0.72

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: rs6339; hg19: chr1-156848946; COSMIC: COSV62324965; COSMIC: COSV62324965;