chr2-1487841-C-T
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001206744.2(TPO):c.1618C>T(p.Arg540Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_001206744.2 stop_gained
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPO | NM_001206744.2 | c.1618C>T | p.Arg540Ter | stop_gained | 10/17 | ENST00000329066.9 | |
LOC124905966 | XR_007086185.1 | n.167-1650G>A | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPO | ENST00000329066.9 | c.1618C>T | p.Arg540Ter | stop_gained | 10/17 | 1 | NM_001206744.2 | P1 | |
ENST00000650512.1 | n.548-69380G>A | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.0000197 AC: 3AN: 152200Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.0000119 AC: 3AN: 251466Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135914
GnomAD4 exome AF: 0.0000233 AC: 34AN: 1461892Hom.: 0 Cov.: 34 AF XY: 0.0000193 AC XY: 14AN XY: 727246
GnomAD4 genome ? AF: 0.0000197 AC: 3AN: 152318Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74478
ClinVar
Submissions by phenotype
not provided Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2022 | TPO: PVS1, PM2, PM3 - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Feb 05, 2019 | The R540X variant in the TPO gene has been reported previously in the homozygous state and in the heterozygous state with a second TPO variant in patients with congenital hypothyroidism; please note that this variant was referred to as c.1708C>T using alternate nomenclature by Bikker et al. (Bikker et al., 1995; Narumi et al., 2011; Cangul et al., 2015). This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The R540X variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). We interpret R540X as a pathogenic variant. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 22, 2023 | This sequence change creates a premature translational stop signal (p.Arg540*) in the TPO gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in TPO are known to be pathogenic (PMID: 11061528, 23236987, 25564141). This variant is present in population databases (rs121908082, gnomAD 0.003%). This premature translational stop signal has been observed in individual(s) with clinical features of thyroid dyshormonogenesis (PMID: 21900383, 34780050). ClinVar contains an entry for this variant (Variation ID: 4042). For these reasons, this variant has been classified as Pathogenic. - |
Deficiency of iodide peroxidase Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 1996 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | 3billion | Jan 03, 2022 | Stop-gained (nonsense): predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant (PVS1_VS). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.000012, PM2_M). The variant has been reported to be associated with TPO related disorder (ClinVar ID: VCV000004042, PMID:7550241).Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at