rs56320207

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_002529.4(NTRK1):c.1331G>A(p.Arg444Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,613,750 control chromosomes in the GnomAD database, including 50 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. R444R) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0093 ( 19 hom., cov: 31)

Exomes 𝑓: 0.0011 ( 31 hom. )

Consequence

NTRK1
NM_002529.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 1.38

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0074874163).

BP6

Variant 1-156874985-G-A is Benign according to our data. Variant chr1-156874985-G-A is described in ClinVar as [Benign]. Clinvar id is 292886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-156874985-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00934 (1421/152188) while in subpopulation AFR AF= 0.0326 (1355/41512). AF 95% confidence interval is 0.0312. There are 19 homozygotes in gnomad4. There are 668 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NTRK1	NM_002529.4 linkuse as main transcript	c.1331G>A	p.Arg444Gln	missense_variant	11/17	ENST00000524377.7	NP_002520.2
NTRK1	NM_001012331.2 linkuse as main transcript	c.1313G>A	p.Arg438Gln	missense_variant	10/16		NP_001012331.1
NTRK1	NM_001007792.1 linkuse as main transcript	c.1223G>A	p.Arg408Gln	missense_variant	11/17		NP_001007793.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 linkuse as main transcript	c.1331G>A	p.Arg444Gln	missense_variant	11/17	1	NM_002529.4	ENSP00000431418	P4	P04629-1

Frequencies

GnomAD3 genomes

AF:

0.00932

AC:

1418

AN:

152070

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0327

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00718

GnomAD3 exomes

AF:

0.00265

AC:

666

AN:

251462

Hom.:

AF XY:

0.00185

AC XY:

251

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.0367

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.00107

AC:

1565

AN:

1461562

Hom.:

Cov.:

AF XY:

0.000912

AC XY:

663

AN XY:

727112

show subpopulations

Gnomad4 AFR exome

AF:

0.0367

Gnomad4 AMR exome

AF:

0.00143

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000900

Gnomad4 OTH exome

AF:

0.00252

GnomAD4 genome

AF:

0.00934

AC:

1421

AN:

152188

Hom.:

Cov.:

AF XY:

0.00898

AC XY:

668

AN XY:

74400

show subpopulations

Gnomad4 AFR

AF:

0.0326

Gnomad4 AMR

AF:

0.00288

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00711

Alfa

AF:

0.00169

Hom.:

Bravo

AF:

0.0109

ESP6500AA

AF:

0.0318

AC:

140

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.00326

AC:

396

Asia WGS

AF:

0.00231

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	Apr 11, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
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	Sep 27, 2021	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 24, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 26, 2021	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.059

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

.;.;D;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.74

LIST_S2

Uncertain

0.89

D;D;D;D

MetaRNN

Benign

0.0075

T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.3

.;.;L;.

MutationTaster

Benign

0.93

N;N;N;N

PrimateAI

Benign

0.20

PROVEAN

Benign

-1.6

N;N;N;N

REVEL

Benign

0.12

Sift

Benign

0.15

T;T;T;T

Sift4G

Benign

0.15

T;T;T;T

Polyphen

0.10, 0.0010

.;B;B;.

Vest4

0.17

MVP

0.85

MPC

0.28

ClinPred

0.0034

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.38

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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