NM_002529.4:c.2046+3A>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3PP5_Moderate

The NM_002529.4(NTRK1):​c.2046+3A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,445,230 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 31)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

NTRK1
NM_002529.4 splice_region, intron

Scores

2
Splicing: ADA: 0.9993
2

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 1.29

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: Uncertain_significance. The variant received 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
PP5
Variant 1-156879365-A-C is Pathogenic according to our data. Variant chr1-156879365-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 12301.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NTRK1NM_002529.4 linkc.2046+3A>C splice_region_variant, intron_variant Intron 15 of 16 ENST00000524377.7 NP_002520.2 P04629-1
NTRK1NM_001012331.2 linkc.2028+3A>C splice_region_variant, intron_variant Intron 14 of 15 NP_001012331.1 P04629-2X5DR71
NTRK1NM_001007792.1 linkc.1938+3A>C splice_region_variant, intron_variant Intron 15 of 16 NP_001007793.1 P04629-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NTRK1ENST00000524377.7 linkc.2046+3A>C splice_region_variant, intron_variant Intron 15 of 16 1 NM_002529.4 ENSP00000431418.1 P04629-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD2 exomes
AF:
0.00000416
AC:
1
AN:
240442
AF XY:
0.00000765
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000290
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000138
AC:
2
AN:
1445230
Hom.:
0
Cov.:
33
AF XY:
0.00000279
AC XY:
2
AN XY:
717958
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33378
American (AMR)
AF:
0.0000448
AC:
2
AN:
44616
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26064
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39528
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86128
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
42884
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5754
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1106876
Other (OTH)
AF:
0.00
AC:
0
AN:
60002
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.450
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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
Cov.:
31
Alfa
AF:
0.00
Hom.:
0

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Hereditary insensitivity to pain with anhidrosis Pathogenic:2
Dec 01, 2001
OMIM
Significance:Pathogenic
Review Status:no assertion criteria provided
Collection Method:literature only

- -

Aug 08, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Pathogenic
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change falls in intron 14 of the NTRK1 gene. It does not directly change the encoded amino acid sequence of the NTRK1 protein. RNA analysis indicates that this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is present in population databases (no rsID available, gnomAD no frequency). This variant has been observed in individuals with NTRK1-related conditions (PMID: 8696348, 19651702; Invitae). It has also been observed to segregate with disease in related individuals. This variant is also known as c.2046+3A>C. ClinVar contains an entry for this variant (Variation ID: 12301). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 8696348). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
CADD
Benign
6.2
DANN
Benign
0.85
PhyloP100
1.3
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Mutation Taster
=2/98
disease causing (ClinVar)

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.86
SpliceAI score (max)
0.93
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.93
Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs914061514; hg19: chr1-156849157; API