rs571832933
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Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5
The ENST00000329066.9(TPO):c.524G>A(p.Arg175Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000118 in 1,613,938 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 Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000012 ( 0 hom. )
Consequence
TPO
ENST00000329066.9 missense
ENST00000329066.9 missense
Scores
11
7
1
Clinical Significance
Conservation
PhyloP100: 8.72
Genes affected
TPO (HGNC:12015): (thyroid peroxidase) This gene encodes a membrane-bound glycoprotein. The encoded protein acts as an enzyme and plays a central role in thyroid gland function. The protein functions in the iodination of tyrosine residues in thyroglobulin and phenoxy-ester formation between pairs of iodinated tyrosines to generate the thyroid hormones, thyroxine and triiodothyronine. Mutations in this gene are associated with several disorders of thyroid hormonogenesis, including congenital hypothyroidism, congenital goiter, and thyroid hormone organification defect IIA. Multiple transcript variants encoding distinct isoforms have been identified for this gene, but the full-length nature of some variants has not been determined. [provided by RefSeq, May 2011]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 2-1453735-G-A is Pathogenic according to our data. Variant chr2-1453735-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 331307.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
TPO | NM_001206744.2 | c.524G>A | p.Arg175Gln | missense_variant | 6/17 | ENST00000329066.9 | NP_001193673.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
TPO | ENST00000329066.9 | c.524G>A | p.Arg175Gln | missense_variant | 6/17 | 1 | NM_001206744.2 | ENSP00000329869 | P1 | |
ENST00000650512.1 | n.548-35274C>T | intron_variant, non_coding_transcript_variant |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152164Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000278 AC: 7AN: 251392Hom.: 0 AF XY: 0.0000442 AC XY: 6AN XY: 135898
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GnomAD4 exome AF: 0.0000116 AC: 17AN: 1461656Hom.: 0 Cov.: 32 AF XY: 0.0000151 AC XY: 11AN XY: 727138
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152282Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1AN XY: 74464
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 01, 2023 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 175 of the TPO protein (p.Arg175Gln). This variant is present in population databases (rs571832933, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of thyroid dyshormonogenesis (PMID: 24790296). 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. ClinVar contains an entry for this variant (Variation ID: 331307). 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: 15279913, 24790296). 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. - |
Deficiency of iodide peroxidase Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 28, 2017 | The TPO c.524G>A (p.Arg175Gln) variant has been reported in one study in which it is found in two siblings with congenital hypothyroidism in a compound heterozygous state with another missense variant (Kotani et al. 2004). Functional studies in CHO cells demonstrated that expression levels of the variant TPO protein were similar to those of the wildtype protein. The variant protein showed reduced localization at plasma membrane in comparision to wildtype with no enzyme activity and insufficient thyroid hormone synthesis (Kotani et al. 2004; Umeki et al. 2004). Control data are unavailable for this variant, which is reported at a frequency 0.00018 in the South Asian population of the Exome Aggregation Consortium. Based on the evidence, the p.Arg175Gln variant is classified as a variant of unknown significance but suspicious for congenital hypothyroidism. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Pathogenic
D;D;.;.;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;H;H;H;H;.
MutationTaster
Benign
N;N;N;N;N;N;N
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D;D;D;D
REVEL
Pathogenic
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D;D
Polyphen
D;D;D;D;D;.
Vest4
MutPred
Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);Loss of MoRF binding (P = 0.0638);.;
MVP
MPC
ClinPred
D
GERP RS
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gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at