rs2280132

Variant names:

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.1117G>T(p.Ala373Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.467 in 1,533,934 control chromosomes in the GnomAD database, including 168,675 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A373A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.43 ( 14593 hom., cov: 34)

Exomes 𝑓: 0.47 ( 154082 hom. )

Consequence

TPO
NM_001206744.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.115

Publications

31 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=2.7723454E-5).

BP6

Variant 2-1477383-G-T is Benign according to our data. Variant chr2-1477383-G-T is described in ClinVar as Benign. ClinVar VariationId is 256605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.1117G>T	p.Ala373Ser	missense_variant	Exon 8 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.1117G>T	p.Ala373Ser	missense_variant	Exon 8 of 17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.435

AC:

66004

AN:

151822

Hom.:

14587

Cov.:

show subpopulations

Gnomad AFR

AF:

0.359

Gnomad AMI

AF:

0.484

Gnomad AMR

AF:

0.447

Gnomad ASJ

AF:

0.435

Gnomad EAS

AF:

0.486

Gnomad SAS

AF:

0.370

Gnomad FIN

AF:

0.436

Gnomad MID

AF:

0.423

Gnomad NFE

AF:

0.479

Gnomad OTH

AF:

0.413

GnomAD2 exomes

AF:

0.470

AC:

61089

AN:

129864

AF XY:

0.466

show subpopulations

Gnomad AFR exome

AF:

0.409

Gnomad AMR exome

AF:

0.499

Gnomad ASJ exome

AF:

0.476

Gnomad EAS exome

AF:

0.504

Gnomad FIN exome

AF:

0.458

Gnomad NFE exome

AF:

0.494

Gnomad OTH exome

AF:

0.474

GnomAD4 exome

AF:

0.471

AC:

650744

AN:

1382004

Hom.:

154082

Cov.:

AF XY:

0.469

AC XY:

319384

AN XY:

681332

show subpopulations

African (AFR)

AF:

0.352

AC:

10766

AN:

30588

American (AMR)

AF:

0.489

AC:

17039

AN:

34878

Ashkenazi Jewish (ASJ)

AF:

0.464

AC:

11419

AN:

24600

East Asian (EAS)

AF:

0.441

AC:

15596

AN:

35328

South Asian (SAS)

AF:

0.386

AC:

30192

AN:

78154

European-Finnish (FIN)

AF:

0.451

AC:

19106

AN:

42354

Middle Eastern (MID)

AF:

0.448

AC:

1971

AN:

4404

European-Non Finnish (NFE)

AF:

0.483

AC:

518487

AN:

1074384

Other (OTH)

AF:

0.457

AC:

26168

AN:

57314

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

22905

45810

68715

91620

114525

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15502

31004

46506

62008

77510

<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:

0.435

AC:

66028

AN:

151930

Hom.:

14593

Cov.:

AF XY:

0.434

AC XY:

32238

AN XY:

74274

show subpopulations

African (AFR)

AF:

0.358

AC:

14855

AN:

41478

American (AMR)

AF:

0.448

AC:

6837

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.435

AC:

1509

AN:

3470

East Asian (EAS)

AF:

0.487

AC:

2492

AN:

5122

South Asian (SAS)

AF:

0.371

AC:

1791

AN:

4830

European-Finnish (FIN)

AF:

0.436

AC:

4610

AN:

10570

Middle Eastern (MID)

AF:

0.424

AC:

123

AN:

290

European-Non Finnish (NFE)

AF:

0.479

AC:

32506

AN:

67878

Other (OTH)

AF:

0.410

AC:

864

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1963

3926

5888

7851

9814

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

618

1236

1854

2472

3090

<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:

0.462

Hom.:

6414

Bravo

AF:

0.435

TwinsUK

AF:

0.482

AC:

1786

ALSPAC

AF:

0.483

AC:

1860

ESP6500AA

AF:

0.316

AC:

871

ESP6500EA

AF:

0.448

AC:

2717

ExAC

AF:

0.361

AC:

25608

Asia WGS

AF:

0.393

AC:

1359

AN:

3454

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

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

- -

Deficiency of iodide peroxidase

Benign:2

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. -

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

0.081

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.18

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.22

T;T;.;.;.

Eigen

Benign

-1.4

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.027

LIST_S2

Benign

0.49

T;.;T;T;T

MetaRNN

Benign

0.000028

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.84

N;N;N;N;.

PhyloP100

0.12

PrimateAI

Uncertain

0.72

PROVEAN

Benign

0.47

N;N;N;N;N

REVEL

Benign

0.038

Sift

Benign

0.92

T;T;T;T;T

Sift4G

Benign

0.90

T;T;T;T;T

Polyphen

0.0050

B;B;B;B;.

Vest4

0.029

MPC

1.1

ClinPred

0.0033

GERP RS

-1.3

Varity_R

0.053

gMVP

0.22

Mutation Taster

=98/2

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