NM_002529.4:c.212+10C>T

Variant summary

Our verdict is Benign. The variant received -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

2

Clinical Significance

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

Conservation

PhyloP100: -0.322

Publications

1 publications found
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 Gene-Disease associations (from GenCC):
  • hereditary sensory and autonomic neuropathy type 4
    Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
  • familial medullary thyroid carcinoma
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 submission is: [Conflicting_classifications_of_pathogenicity].
BS2
High Homozygotes in GnomAdExome4 at 3 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK1NM_002529.4 linkc.212+10C>T intron_variant Intron 1 of 16 ENST00000524377.7 NP_002520.2 P04629-1
NTRK1NM_001012331.2 linkc.212+10C>T intron_variant Intron 1 of 15 NP_001012331.1 P04629-2X5DR71
NTRK1NM_001007792.1 linkc.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
NTRK1ENST00000524377.7 linkc.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.:
0
Cov.:
33
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
GnomAD2 exomes
AF:
0.00114
AC:
170
AN:
149738
AF XY:
0.00104
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 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.:
3
Cov.:
32
AF XY:
0.00156
AC XY:
1077
AN XY:
692442
show subpopulations
African (AFR)
AF:
0.000216
AC:
7
AN:
32342
American (AMR)
AF:
0.00223
AC:
85
AN:
38110
Ashkenazi Jewish (ASJ)
AF:
0.0000789
AC:
2
AN:
25334
East Asian (EAS)
AF:
0.00
AC:
0
AN:
37132
South Asian (SAS)
AF:
0.0000497
AC:
4
AN:
80446
European-Finnish (FIN)
AF:
0.0000772
AC:
3
AN:
38876
Middle Eastern (MID)
AF:
0.000981
AC:
5
AN:
5096
European-Non Finnish (NFE)
AF:
0.00186
AC:
2013
AN:
1084836
Other (OTH)
AF:
0.00144
AC:
84
AN:
58204
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
128
257
385
514
642
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
80
160
240
320
400
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.00110
AC:
167
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.00107
AC XY:
80
AN XY:
74486
show subpopulations
African (AFR)
AF:
0.000361
AC:
15
AN:
41562
American (AMR)
AF:
0.00261
AC:
40
AN:
15308
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3468
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5176
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10622
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00156
AC:
106
AN:
68026
Other (OTH)
AF:
0.00284
AC:
6
AN:
2116
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.493
Heterozygous variant carriers
0
8
16
24
32
40
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
4
8
12
16
20
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.00162
Hom.:
0
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
Jan 26, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Apr 17, 2020
Natera, Inc.
Significance:Uncertain significance
Review Status:no assertion criteria provided
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 DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic 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
PhyloP100
-0.32
PromoterAI
-0.00060
Neutral
Mutation Taster
=100/0
polymorphism

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

Other links and lift over

dbSNP: rs183517027; hg19: chr1-156830948; API