NM_001206744.2:c.2540T>C

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.2540T>C(p.Val847Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,542 control chromosomes in the GnomAD database, including 256,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V847M) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.62 ( 30292 hom., cov: 33)

Exomes 𝑓: 0.55 ( 226423 hom. )

Consequence

TPO
NM_001206744.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.630

Publications

39 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=2.9479213E-6).

BP6

Variant 2-1516904-T-C is Benign according to our data. Variant chr2-1516904-T-C is described in ClinVar as Benign. ClinVar VariationId is 256614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.2540T>C	p.Val847Ala	missense_variant	Exon 15 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.2540T>C	p.Val847Ala	missense_variant	Exon 15 of 17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.622

AC:

94584

AN:

151998

Hom.:

30241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.778

Gnomad AMI

AF:

0.520

Gnomad AMR

AF:

0.613

Gnomad ASJ

AF:

0.505

Gnomad EAS

AF:

0.597

Gnomad SAS

AF:

0.656

Gnomad FIN

AF:

0.613

Gnomad MID

AF:

0.506

Gnomad NFE

AF:

0.539

Gnomad OTH

AF:

0.586

GnomAD2 exomes

AF:

0.587

AC:

147233

AN:

250810

AF XY:

0.583

show subpopulations

Gnomad AFR exome

AF:

0.783

Gnomad AMR exome

AF:

0.621

Gnomad ASJ exome

AF:

0.480

Gnomad EAS exome

AF:

0.587

Gnomad FIN exome

AF:

0.609

Gnomad NFE exome

AF:

0.537

Gnomad OTH exome

AF:

0.551

GnomAD4 exome

AF:

0.554

AC:

808956

AN:

1461426

Hom.:

226423

Cov.:

AF XY:

0.555

AC XY:

403796

AN XY:

727020

show subpopulations

African (AFR)

AF:

0.791

AC:

26480

AN:

33478

American (AMR)

AF:

0.619

AC:

27685

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

12685

AN:

26136

East Asian (EAS)

AF:

0.623

AC:

24739

AN:

39698

South Asian (SAS)

AF:

0.651

AC:

56113

AN:

86252

European-Finnish (FIN)

AF:

0.602

AC:

31947

AN:

53078

Middle Eastern (MID)

AF:

0.479

AC:

2760

AN:

5762

European-Non Finnish (NFE)

AF:

0.533

AC:

592487

AN:

1111916

Other (OTH)

AF:

0.564

AC:

34060

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

22421

44843

67264

89686

112107

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

17002

34004

51006

68008

85010

<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:

0.623

AC:

94699

AN:

152116

Hom.:

30292

Cov.:

AF XY:

0.624

AC XY:

46406

AN XY:

74370

show subpopulations

African (AFR)

AF:

0.779

AC:

32323

AN:

41506

American (AMR)

AF:

0.613

AC:

9368

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.505

AC:

1750

AN:

3468

East Asian (EAS)

AF:

0.598

AC:

3078

AN:

5150

South Asian (SAS)

AF:

0.656

AC:

3168

AN:

4832

European-Finnish (FIN)

AF:

0.613

AC:

6492

AN:

10584

Middle Eastern (MID)

AF:

0.514

AC:

151

AN:

294

European-Non Finnish (NFE)

AF:

0.539

AC:

36656

AN:

67986

Other (OTH)

AF:

0.587

AC:

1239

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1770

3540

5311

7081

8851

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

778

1556

2334

3112

3890

<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:

0.559

Hom.:

101228

Bravo

AF:

0.626

TwinsUK

AF:

0.519

AC:

1923

ALSPAC

AF:

0.526

AC:

2028

ESP6500AA

AF:

0.771

AC:

3398

ESP6500EA

AF:

0.532

AC:

4578

ExAC

AF:

0.589

AC:

71519

Asia WGS

AF:

0.655

AC:

2276

AN:

3478

EpiCase

AF:

0.527

EpiControl

AF:

0.522

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

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

- -

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

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:3

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

- -

Nov 12, 2018

GeneDx

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.54

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.6

(source)

DANN

Benign

0.19

DEOGEN2

Benign

0.26

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

Eigen

Benign

-0.79

Eigen_PC

Benign

-0.74

FATHMM_MKL

Benign

0.0011

LIST_S2

Benign

0.28

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

MetaRNN

Benign

0.0000029

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

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.6

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

PhyloP100

0.63

PrimateAI

Benign

0.41

PROVEAN

Benign

1.7

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

REVEL

Uncertain

0.32

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

0.036

MPC

0.19

ClinPred

0.011

GERP RS

4.6

Varity_R

0.033

gMVP

0.59

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