rs80356674
Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong
The NM_002529.4(NTRK1):c.851-33T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000125 in 1,443,816 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). There are indicators that this mutation may affect the branch point..
Frequency
Consequence
NM_002529.4 intron
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 10 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NTRK1 | NM_002529.4 | c.851-33T>A | intron_variant | ENST00000524377.7 | |||
NTRK1 | NM_001007792.1 | c.761-33T>A | intron_variant | ||||
NTRK1 | NM_001012331.2 | c.851-33T>A | intron_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NTRK1 | ENST00000524377.7 | c.851-33T>A | intron_variant | 1 | NM_002529.4 | P4 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD3 exomes AF: 0.0000340 AC: 8AN: 235406Hom.: 0 AF XY: 0.0000232 AC XY: 3AN XY: 129462
GnomAD4 exome AF: 0.0000125 AC: 18AN: 1443816Hom.: 0 Cov.: 31 AF XY: 0.0000139 AC XY: 10AN XY: 718650
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Hereditary insensitivity to pain with anhidrosis Pathogenic:5Other:1
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Oct 02, 2021 | Intron variant: previously reported to alter splicing and result in a loss of normal protein fucnction through nonsense-mediated decay (NMD) or protein truncation (PMID: 10982191, PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000340, PM2). The variant was observed in trans with a pathogenic variant (NM_002529.3:c.2020G>T) as compound heterozygous (3billion dataset, PM3).The variant has been reported to co-segregate with the disease in at least 3 similarly affected relatives/individuals in the same family or similarly affected unrelated family (PMID: 27265460 and 28345382, PP1_M). Patient's phenotype is considered compatible with Insensitivity to pain, congenital, with anhidrosis (3billion dataset, PP4).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 17, 2024 | This sequence change falls in intron 7 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 (rs80356674, gnomAD 0.05%). This variant has been observed in individual(s) with congenital insensitivity to pain with anhidrosis (CIPA) (PMID: 10982191, 19618435, 23112235, 27265460, 28345382, 29619836). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. This variant is also known as IVS7-33T>A and c.935-33T>A. ClinVar contains an entry for this variant (Variation ID: 21308). Studies have shown that this variant results in retention of 137 nucleotides from intron 7 and introduces a premature termination codon (PMID: 10982191). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Apr 11, 2023 | - - |
not provided, no classification provided | literature only | GeneReviews | - | Common pathogenic variant in Japanese, Korean, and Chinese populations. - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Jan 01, 2000 | - - |
Pathogenic, no assertion criteria provided | clinical testing | Natera, Inc. | Sep 16, 2020 | - - |
Inborn genetic diseases Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jan 21, 2014 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Dec 14, 2022 | Published functional studies demonstrate a damaging effect (activation of upstream cryptic splice acceptor site resulting in aberrant splicing in vitro and incorporation of an abberant fragment into the mRNA) (Miura et al., 2000); Not observed at a significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23112235, 30774415, 34674383, 34938316, 25356970, 28345382, 19618435, 27265460, 29770739, 30201336, 29619836, 31857517, 32219930, 30677517, 33422294, 33748046, 32901917, 10982191) - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at