2-1487841-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.Arg540*) 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
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ACMG classification
Verdict is Pathogenic. Variant got 18 ACMG points.
Transcripts
RefSeq
Ensembl
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
Deficiency of iodide peroxidase Pathogenic:3
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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. -
not provided Pathogenic:3
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. -
Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 21900383, 25525159, 7550241, 8964831, 26777044, 34426522, 32459320, 33298898, 33368191, 39003160, 38986456, 34501348, 31256877, 31980526, 38105685, 34780050, 34200080, 36913313) -
TPO: PVS1, PM2, PM3 -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at