rs55909005

chr1-156868640-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002529.4(NTRK1):c.710C>T(p.Thr237Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00315 in 1,550,790 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T237A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.016 (72 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (60 hom.)
• Consequence: NTRK1 NM_002529.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.347

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002357781).
• BP6: Variant 1-156868640-C-T is Benign according to our data. Variant chr1-156868640-C-T is described in ClinVar as [Benign]. Clinvar id is 198111.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156868640-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.055 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NTRK1	NM_002529.4	c.710C>T	p.Thr237Met	missense_variant	6/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.710C>T	p.Thr237Met	missense_variant	6/16
NTRK1	NM_001007792.1	c.620C>T	p.Thr207Met	missense_variant	7/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NTRK1	ENST00000524377.7	c.710C>T	p.Thr237Met	missense_variant	6/17	1	NM_002529.4	P4

Frequencies

GnomAD3 genomes AF: 0.0164 AC: 2497 AN: 152164 Hom.: 72 Cov.: 33

Gnomad AFR AF: 0.0570

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00694

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00909

GnomAD3 exomes AF: 0.00401 AC: 619 AN: 154444 Hom.: 14 AF XY: 0.00317 AC XY: 259 AN XY: 81610

Gnomad AFR exome AF: 0.0578

Gnomad AMR exome AF: 0.00388

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000263

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000671

Gnomad OTH exome AF: 0.00364

GnomAD4 exome AF: 0.00170 AC: 2381 AN: 1398508 Hom.: 60 Cov.: 33 AF XY: 0.00149 AC XY: 1031 AN XY: 689830

Gnomad4 AFR exome AF: 0.0580

Gnomad4 AMR exome AF: 0.00434

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000379

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000102

Gnomad4 OTH exome AF: 0.00405

GnomAD4 genome AF: 0.0164 AC: 2500 AN: 152282 Hom.: 72 Cov.: 33 AF XY: 0.0157 AC XY: 1168 AN XY: 74464

Gnomad4 AFR AF: 0.0569

Gnomad4 AMR AF: 0.00693

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.00825 Hom.: 20

Bravo AF: 0.0185

ESP6500AA AF: 0.0479 AC: 196

ESP6500EA AF: 0.000623 AC: 5

ExAC AF: 0.00316 AC: 225

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:7

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Apr 11, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Counsyl	Mar 06, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 22, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 26, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2015	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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Sep 28, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	18
Dann	Uncertain	1.0
Eigen	Benign	-0.11
Eigen_PC	Benign	-0.23
FATHMM_MKL	Benign	0.18	N
LIST_S2	Uncertain	0.87	D;D;D;D
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	0.84	N;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.046
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.19	T;T;T;T
Polyphen		1.0	.;D;D;.
Vest4		0.25
MVP		0.90
MPC		0.29
ClinPred		0.0054	T
GERP RS		2.5
Varity_R		0.035
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs55909005; hg19: chr1-156838432; COSMIC: COSV62325267; COSMIC: COSV62325267;