rs6334

chr1-156876441-G-Achr1-156876441-G-Cchr1-156876441-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.221

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 -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	UniProt
NTRK1	NM_002529.4	c.1674G>A	p.Gln558=	synonymous_variant	14/17	ENST00000524377.7
NTRK1	NM_001012331.2	c.1656G>A	p.Gln552=	synonymous_variant	13/16
NTRK1	NM_001007792.1	c.1566G>A	p.Gln522=	synonymous_variant	14/17

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.201 AC: 30552 AN: 152072 Hom.: 3221 Cov.: 32

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

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.: 41 AF XY: 0.222 AC XY: 161355 AN XY: 727046

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.: 32 AF XY: 0.203 AC XY: 15080 AN XY: 74398

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:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Benign:5

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	Genome-Nilou Lab	Jul 01, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not specified Benign:4

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	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 28, 2017	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

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

Other links and lift over

dbSNP: rs6334; hg19: chr1-156846233; COSMIC: COSV62323674; COSMIC: COSV62323674;