rs140124953
Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM2PM5PP3_ModeratePP5_Very_Strong
The NM_001206744.2(TPO):c.1994G>A(p.Arg665Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000157 in 1,461,770 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 Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R665W) has been classified as Pathogenic.
Frequency
Consequence
NM_001206744.2 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 14 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TPO | NM_001206744.2 | c.1994G>A | p.Arg665Gln | missense_variant | 11/17 | ENST00000329066.9 | |
LOC124905966 | XR_007086185.1 | n.167-7836C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TPO | ENST00000329066.9 | c.1994G>A | p.Arg665Gln | missense_variant | 11/17 | 1 | NM_001206744.2 | P1 | |
ENST00000650512.1 | n.548-75566C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes ? AF: 0.00 AC: 0AN: 152162Hom.: 0 Cov.: 33 FAILED QC
GnomAD3 exomes AF: 0.0000279 AC: 7AN: 250664Hom.: 0 AF XY: 0.0000295 AC XY: 4AN XY: 135592
GnomAD4 exome AF: 0.0000157 AC: 23AN: 1461770Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 16AN XY: 727178
GnomAD4 genome ? Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 152162Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74332
ClinVar
Submissions by phenotype
Deficiency of iodide peroxidase Pathogenic:2
Pathogenic, no assertion criteria provided | clinical testing | Baylor Genetics | Jun 10, 2015 | Our laboratory reported dual molecular diagnoses in TPO (NM_000547.4, c.1994G>A) and MMP2 (NM_004530.4, c.539A>T) in an individual with reported features of congenital hypothyroidism, multiple joint swellings and contractures, skin anomalies (brown skin pigmentation on side of abdomen & right upper arm), and hypospadias. The TPO variant has been previously reported as disease-causing (PMID 14751036, 11916616). Heterozygotes are expected to be asymptomatic carriers. - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 22, 2022 | - - |
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Invitae | Oct 23, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 665 of the TPO protein (p.Arg665Gln). This variant is present in population databases (rs140124953, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of TPO-related conditions (PMID: 11916616, 14751036, 27060741, 27525530, 30240412, 32078117). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 374344). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on TPO protein function. Experimental studies have shown that this missense change affects TPO function (PMID: 32078117). This variant disrupts the p.Arg665 amino acid residue in TPO. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 24790296, 34220711). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at