1-156861156-C-T

Variant names:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_002529.4(NTRK1):c.212+10C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00153 in 1,552,690 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0011 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0016 ( 3 hom. )

Consequence

NTRK1
NM_002529.4 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:4

Conservation

PhyloP100: -0.322

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 -9 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.74).

BP6

Variant 1-156861156-C-T is Benign according to our data. Variant chr1-156861156-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 292872.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1}. Variant chr1-156861156-C-T is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
NTRK1	NM_002529.4 link	c.212+10C>T	intron_variant	Intron 1 of 16	ENST00000524377.7	NP_002520.2	P04629-1
NTRK1	NM_001012331.2 link	c.212+10C>T	intron_variant	Intron 1 of 15		NP_001012331.1	P04629-2X5DR71
NTRK1	NM_001007792.1 link	c.123-3198C>T	intron_variant	Intron 2 of 16		NP_001007793.1	P04629-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NTRK1	ENST00000524377.7 link	c.212+10C>T		intron_variant	Intron 1 of 16	1	NM_002529.4	ENSP00000431418.1		P04629-1

Frequencies

GnomAD3 genomes

AF:

0.00110

AC:

167

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000362

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00156

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00114

AC:

170

AN:

149738

Hom.:

AF XY:

0.00104

AC XY:

AN XY:

82360

show subpopulations

Gnomad AFR exome

AF:

0.000124

Gnomad AMR exome

AF:

0.00175

Gnomad ASJ exome

AF:

0.000120

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000845

Gnomad FIN exome

AF:

0.000116

Gnomad NFE exome

AF:

0.00197

Gnomad OTH exome

AF:

0.00116

GnomAD4 exome

AF:

0.00157

AC:

2203

AN:

1400376

Hom.:

Cov.:

AF XY:

0.00156

AC XY:

1077

AN XY:

692442

show subpopulations

Gnomad4 AFR exome

AF:

0.000216

Gnomad4 AMR exome

AF:

0.00223

Gnomad4 ASJ exome

AF:

0.0000789

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000497

Gnomad4 FIN exome

AF:

0.0000772

Gnomad4 NFE exome

AF:

0.00186

Gnomad4 OTH exome

AF:

0.00144

GnomAD4 genome

AF:

0.00110

AC:

167

AN:

152314

Hom.:

Cov.:

AF XY:

0.00107

AC XY:

AN XY:

74486

show subpopulations

Gnomad4 AFR

AF:

0.000361

Gnomad4 AMR

AF:

0.00261

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00156

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00162

Hom.:

Bravo

AF:

0.00155

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis

Uncertain:2Benign:1

Apr 17, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided

Benign:2

Clinical Genetics, Academic Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not specified

Benign:1

Apr 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.74

CADD

Benign

4.6

DANN

Benign

0.94

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