rs571832933

Positions:

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_001206744.2(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
NM_001206744.2 missense

Scores

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]

TPO links:

TPO (HGNC:):

TPO links:

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: {Uncertain_significance=1, Likely_pathogenic=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	6/17	ENST00000329066.9	NP_001193673.1	P07202-1Q502Y3Q6P534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9 linkuse as main transcript	c.524G>A	p.Arg175Gln	missense_variant	6/17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

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:

AN:

251392

Hom.:

AF XY:

0.0000442

AC XY:

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:

AN:

1461656

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

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:

AN:

152282

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

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.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000247

AC:

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.89

D;D;.;.;.;.

Eigen

Pathogenic

0.76

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;.;D;D;D;D

M_CAP

Pathogenic

0.58

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D

MetaSVM

Pathogenic

0.97

MutationAssessor

Pathogenic

4.2

H;H;H;H;H;.

PrimateAI

Uncertain

0.64

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over