rs6334

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_002529.4(NTRK1):c.1674G>A(p.Gln558=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 1,613,668 control chromosomes in the GnomAD database, including 39,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.20 ( 3219 hom., cov: 32)

Exomes 𝑓: 0.22 ( 36528 hom. )

Consequence

NTRK1
NM_002529.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.221

Variant links:

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]

NTRK1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.53).

BP6

Variant 1-156876441-G-A is Benign according to our data. Variant chr1-156876441-G-A is described in ClinVar as [Benign]. Clinvar id is 292889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156876441-G-A is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.221 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NTRK1	NM_002529.4 linkuse as main transcript	c.1674G>A	p.Gln558=	synonymous_variant	14/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 linkuse as main transcript	c.1656G>A	p.Gln552=	synonymous_variant	13/16		NP_001012331.1
NTRK1	NM_001007792.1 linkuse as main transcript	c.1566G>A	p.Gln522=	synonymous_variant	14/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.1674G>A	p.Gln558=	synonymous_variant	14/17	1	NM_002529.4	ENSP00000431418	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.201

AC:

30552

AN:

152072

Hom.:

3221

Cov.:

show subpopulations

Gnomad AFR

AF:

0.139

Gnomad AMI

AF:

0.249

Gnomad AMR

AF:

0.226

Gnomad ASJ

AF:

0.209

Gnomad EAS

AF:

0.346

Gnomad SAS

AF:

0.240

Gnomad FIN

AF:

0.202

Gnomad MID

AF:

0.177

Gnomad NFE

AF:

0.218

Gnomad OTH

AF:

0.212

GnomAD3 exomes

AF:

0.220

AC:

55246

AN:

250768

Hom.:

6397

AF XY:

0.223

AC XY:

30238

AN XY:

135714

show subpopulations

Gnomad AFR exome

AF:

0.131

Gnomad AMR exome

AF:

0.216

Gnomad ASJ exome

AF:

0.198

Gnomad EAS exome

AF:

0.349

Gnomad SAS exome

AF:

0.235

Gnomad FIN exome

AF:

0.202

Gnomad NFE exome

AF:

0.214

Gnomad OTH exome

AF:

0.228

GnomAD4 exome

AF:

0.221

AC:

322889

AN:

1461478

Hom.:

36528

Cov.:

AF XY:

0.222

AC XY:

161355

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.131

Gnomad4 AMR exome

AF:

0.216

Gnomad4 ASJ exome

AF:

0.196

Gnomad4 EAS exome

AF:

0.356

Gnomad4 SAS exome

AF:

0.235

Gnomad4 FIN exome

AF:

0.201

Gnomad4 NFE exome

AF:

0.219

Gnomad4 OTH exome

AF:

0.224

GnomAD4 genome

AF:

0.201

AC:

30560

AN:

152190

Hom.:

3219

Cov.:

AF XY:

0.203

AC XY:

15080

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.138

Gnomad4 AMR

AF:

0.226

Gnomad4 ASJ

AF:

0.209

Gnomad4 EAS

AF:

0.345

Gnomad4 SAS

AF:

0.241

Gnomad4 FIN

AF:

0.202

Gnomad4 NFE

AF:

0.218

Gnomad4 OTH

AF:

0.213

Alfa

AF:

0.205

Hom.:

5535

Bravo

AF:

0.200

Asia WGS

AF:

0.283

AC:

984

AN:

3478

EpiCase

AF:

0.217

EpiControl

AF:

0.212

ClinVar

Significance: Benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Benign:5

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 01, 2021	- -
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. -
Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.53

CADD

Benign

9.2

DANN

Benign

0.93

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over