rs80356676
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002529.4(NTRK1):c.1860_1861insT(p.Pro621SerfsTer12) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,070 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: 𝑓 0.000039 ( 1 hom., cov: 31)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
NTRK1
NM_002529.4 frameshift
NM_002529.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 0.763
Publications
8 publications found
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 4Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- familial medullary thyroid carcinomaInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
Genome browser will be placed here
ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 16 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PP5
Variant 1-156879176-C-CT is Pathogenic according to our data. Variant chr1-156879176-C-CT is described in ClinVar as Pathogenic. ClinVar VariationId is 21306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_002529.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NTRK1 | MANE Select | c.1860_1861insT | p.Pro621SerfsTer12 | frameshift | Exon 15 of 17 | NP_002520.2 | |||
| NTRK1 | c.1842_1843insT | p.Pro615SerfsTer12 | frameshift | Exon 14 of 16 | NP_001012331.1 | P04629-2 | |||
| NTRK1 | c.1752_1753insT | p.Pro585SerfsTer12 | frameshift | Exon 15 of 17 | NP_001007793.1 | P04629-3 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| NTRK1 | TSL:1 MANE Select | c.1860_1861insT | p.Pro621SerfsTer12 | frameshift | Exon 15 of 17 | ENSP00000431418.1 | P04629-1 | ||
| NTRK1 | TSL:1 | c.1842_1843insT | p.Pro615SerfsTer12 | frameshift | Exon 14 of 16 | ENSP00000357179.3 | P04629-2 | ||
| NTRK1 | TSL:2 | c.1851_1852insT | p.Pro618SerfsTer12 | frameshift | Exon 14 of 16 | ENSP00000351486.3 | J3KP20 |
Frequencies
GnomAD3 genomes 0.0000395 AC: 6AN: 152088Hom.: 1 Cov.: 31 show subpopulations
GnomAD3 genomes
AF:
AC:
6
AN:
152088
Hom.:
Cov.:
31
Gnomad AFR
AF:
Gnomad AMI
AF:
Gnomad AMR
AF:
Gnomad ASJ
AF:
Gnomad EAS
AF:
Gnomad SAS
AF:
Gnomad FIN
AF:
Gnomad MID
AF:
Gnomad NFE
AF:
Gnomad OTH
AF:
GnomAD4 exome AF: 6.85e-7 AC: 1AN: 1460864Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 726718 show subpopulations
GnomAD4 exome
AF:
AC:
1
AN:
1460864
Hom.:
Cov.:
32
AF XY:
AC XY:
1
AN XY:
726718
show subpopulations
African (AFR)
AF:
AC:
0
AN:
33472
American (AMR)
AF:
AC:
0
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26118
East Asian (EAS)
AF:
AC:
0
AN:
39694
South Asian (SAS)
AF:
AC:
0
AN:
86202
European-Finnish (FIN)
AF:
AC:
0
AN:
53400
Middle Eastern (MID)
AF:
AC:
1
AN:
5758
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111164
Other (OTH)
AF:
AC:
0
AN:
60354
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
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
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6
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<30
30-35
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>80
Age
GnomAD4 genome 0.0000394 AC: 6AN: 152206Hom.: 1 Cov.: 31 AF XY: 0.0000134 AC XY: 1AN XY: 74434 show subpopulations
GnomAD4 genome
AF:
AC:
6
AN:
152206
Hom.:
Cov.:
31
AF XY:
AC XY:
1
AN XY:
74434
show subpopulations
African (AFR)
AF:
AC:
0
AN:
41516
American (AMR)
AF:
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
3470
East Asian (EAS)
AF:
AC:
0
AN:
5162
South Asian (SAS)
AF:
AC:
0
AN:
4820
European-Finnish (FIN)
AF:
AC:
0
AN:
10610
Middle Eastern (MID)
AF:
AC:
6
AN:
294
European-Non Finnish (NFE)
AF:
AC:
0
AN:
68018
Other (OTH)
AF:
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.563
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
ClinVar
ClinVar submissions
View on ClinVar Significance:Pathogenic
Revision:criteria provided, multiple submitters, no conflicts
Pathogenic
VUS
Benign
Condition
6
-
-
Hereditary insensitivity to pain with anhidrosis (7)
1
-
-
not provided (1)
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
PhyloP100
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
Publications
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