rs732609

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001206744.2(TPO):c.2173A>C(p.Thr725Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.418 in 1,612,876 control chromosomes in the GnomAD database, including 144,001 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.47 ( 17340 hom., cov: 33)

Exomes 𝑓: 0.41 ( 126661 hom. )

Consequence

TPO
NM_001206744.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 2.92

Publications

53 publications found

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 Gene-Disease associations (from GenCC):

thyroid dyshormonogenesis 2A
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
familial thyroid dyshormonogenesis
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TPO links:

ENSG00000231482 (HGNC:):

ENSG00000231482 links:

ENSG00000228613 (HGNC:58132):

ENSG00000228613 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2536894E-5).

BP6

Variant 2-1496155-A-C is Benign according to our data. Variant chr2-1496155-A-C is described in ClinVar as Benign. ClinVar VariationId is 256611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.2173A>C	p.Thr725Pro	missense_variant	Exon 12 of 17	ENST00000329066.9	NP_001193673.1	P07202-1Q502Y3Q6P534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9 link	c.2173A>C	p.Thr725Pro	missense_variant	Exon 12 of 17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.468

AC:

71154

AN:

152012

Hom.:

17306

Cov.:

show subpopulations

Gnomad AFR

AF:

0.606

Gnomad AMI

AF:

0.401

Gnomad AMR

AF:

0.473

Gnomad ASJ

AF:

0.375

Gnomad EAS

AF:

0.418

Gnomad SAS

AF:

0.499

Gnomad FIN

AF:

0.420

Gnomad MID

AF:

0.373

Gnomad NFE

AF:

0.398

Gnomad OTH

AF:

0.473

GnomAD2 exomes

AF:

0.429

AC:

107012

AN:

249642

AF XY:

0.426

show subpopulations

Gnomad AFR exome

AF:

0.605

Gnomad AMR exome

AF:

0.446

Gnomad ASJ exome

AF:

0.364

Gnomad EAS exome

AF:

0.411

Gnomad FIN exome

AF:

0.413

Gnomad NFE exome

AF:

0.389

Gnomad OTH exome

AF:

0.412

GnomAD4 exome

AF:

0.413

AC:

603712

AN:

1460746

Hom.:

126661

Cov.:

AF XY:

0.415

AC XY:

301409

AN XY:

726548

show subpopulations

African (AFR)

AF:

0.625

AC:

20926

AN:

33466

American (AMR)

AF:

0.449

AC:

20002

AN:

44586

Ashkenazi Jewish (ASJ)

AF:

0.367

AC:

9591

AN:

26122

East Asian (EAS)

AF:

0.451

AC:

17885

AN:

39658

South Asian (SAS)

AF:

0.501

AC:

43101

AN:

86088

European-Finnish (FIN)

AF:

0.412

AC:

21972

AN:

53306

Middle Eastern (MID)

AF:

0.383

AC:

2200

AN:

5748

European-Non Finnish (NFE)

AF:

0.398

AC:

442258

AN:

1111442

Other (OTH)

AF:

0.427

AC:

25777

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

22912

45823

68735

91646

114558

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13924

27848

41772

55696

69620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.468

AC:

71243

AN:

152130

Hom.:

17340

Cov.:

AF XY:

0.468

AC XY:

34844

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.607

AC:

25183

AN:

41498

American (AMR)

AF:

0.473

AC:

7230

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.375

AC:

1299

AN:

3468

East Asian (EAS)

AF:

0.418

AC:

2153

AN:

5156

South Asian (SAS)

AF:

0.498

AC:

2403

AN:

4824

European-Finnish (FIN)

AF:

0.420

AC:

4451

AN:

10600

Middle Eastern (MID)

AF:

0.378

AC:

111

AN:

294

European-Non Finnish (NFE)

AF:

0.398

AC:

27054

AN:

67978

Other (OTH)

AF:

0.470

AC:

994

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1914

3828

5742

7656

9570

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

652

1304

1956

2608

3260

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.417

Hom.:

45840

Bravo

AF:

0.474

TwinsUK

AF:

0.395

AC:

1464

ALSPAC

AF:

0.396

AC:

1527

ESP6500AA

AF:

0.607

AC:

2676

ESP6500EA

AF:

0.400

AC:

3441

ExAC

AF:

0.429

AC:

52123

Asia WGS

AF:

0.471

AC:

1637

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Deficiency of iodide peroxidase

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

May 28, 2019

Mendelics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.12

DEOGEN2

Benign

0.29

T;T;.;.;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.028

LIST_S2

Benign

0.025

T;.;T;T;T;T;T

MetaRNN

Benign

0.000013

T;T;T;T;T;T;T

MetaSVM

Benign

-0.91

MutationAssessor

Benign

-2.2

N;N;.;N;.;.;.

PhyloP100

2.9

PrimateAI

Benign

0.40

PROVEAN

Benign

6.0

N;N;N;N;N;N;N

REVEL

Benign

0.26

Sift

Benign

1.0

T;T;T;T;T;T;T

Sift4G

Benign

1.0

T;T;T;T;T;T;T

Polyphen

0.0

B;B;B;B;B;.;.

Vest4

0.047

MPC

0.21

ClinPred

0.0052

GERP RS

4.4

Varity_R

0.093

gMVP

0.68

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over