rs571832933

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

Scores

11
7
1

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:1

Conservation

PhyloP100: 8.72
Variant links:
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]

Genome browser will be placed here

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
TPONM_001206744.2 linkuse as main transcriptc.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
TPOENST00000329066.9 linkuse as main transcriptc.524G>A p.Arg175Gln missense_variant 6/171 NM_001206744.2 ENSP00000329869 P1P07202-1
ENST00000650512.1 linkuse as main transcriptn.548-35274C>T intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152164
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000278
AC:
7
AN:
251392
Hom.:
0
AF XY:
0.0000442
AC XY:
6
AN XY:
135898
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000163
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000116
AC:
17
AN:
1461656
Hom.:
0
Cov.:
32
AF XY:
0.0000151
AC XY:
11
AN XY:
727138
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000139
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000450
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152282
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000278
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.0000247
AC:
3

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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 01, 2023This 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 submitterclinical testingIllumina Laboratory Services, IlluminaApr 28, 2017The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.41
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.40
CADD
Pathogenic
28
DANN
Pathogenic
1.0
DEOGEN2
Pathogenic
0.89
D;D;.;.;.;.
Eigen
Pathogenic
0.76
Eigen_PC
Uncertain
0.60
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.97
D;.;D;D;D;D
M_CAP
Pathogenic
0.58
D
MetaRNN
Pathogenic
0.99
D;D;D;D;D;D
MetaSVM
Pathogenic
0.97
D
MutationAssessor
Pathogenic
4.2
H;H;H;H;H;.
MutationTaster
Benign
0.66
N;N;N;N;N;N;N
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.3
D;D;D;D;D;D
REVEL
Pathogenic
0.84
Sift
Uncertain
0.0010
D;D;D;D;D;D
Sift4G
Uncertain
0.0030
D;D;D;D;D;D
Polyphen
1.0
D;D;D;D;D;.
Vest4
0.94
MutPred
0.96
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
0.97
MPC
0.77
ClinPred
0.97
D
GERP RS
5.3
Varity_R
0.83
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs571832933; hg19: chr2-1457507; COSMIC: COSV61104704; COSMIC: COSV61104704; API