rs9678281

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001206744.2(TPO):c.12C>G(p.Leu4Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,611,858 control chromosomes in the GnomAD database, including 113,519 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L4L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.36 ( 10159 hom., cov: 32)

Exomes 𝑓: 0.37 ( 103360 hom. )

Consequence

TPO
NM_001206744.2 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: -3.72

Publications

19 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.98).

BP6

Variant 2-1414420-C-G is Benign according to our data. Variant chr2-1414420-C-G is described in ClinVar as Benign. ClinVar VariationId is 256607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-3.72 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.408 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.12C>G	p.Leu4Leu	synonymous_variant	Exon 2 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.12C>G	p.Leu4Leu	synonymous_variant	Exon 2 of 17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.358

AC:

54395

AN:

151876

Hom.:

10154

Cov.:

show subpopulations

Gnomad AFR

AF:

0.292

Gnomad AMI

AF:

0.422

Gnomad AMR

AF:

0.416

Gnomad ASJ

AF:

0.361

Gnomad EAS

AF:

0.208

Gnomad SAS

AF:

0.336

Gnomad FIN

AF:

0.414

Gnomad MID

AF:

0.291

Gnomad NFE

AF:

0.389

Gnomad OTH

AF:

0.353

GnomAD2 exomes

AF:

0.365

AC:

91287

AN:

249830

AF XY:

0.363

show subpopulations

Gnomad AFR exome

AF:

0.292

Gnomad AMR exome

AF:

0.411

Gnomad ASJ exome

AF:

0.339

Gnomad EAS exome

AF:

0.206

Gnomad FIN exome

AF:

0.415

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.377

GnomAD4 exome

AF:

0.374

AC:

545769

AN:

1459864

Hom.:

103360

Cov.:

AF XY:

0.373

AC XY:

270594

AN XY:

726262

show subpopulations

African (AFR)

AF:

0.286

AC:

9574

AN:

33452

American (AMR)

AF:

0.411

AC:

18331

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.339

AC:

8855

AN:

26110

East Asian (EAS)

AF:

0.203

AC:

8040

AN:

39686

South Asian (SAS)

AF:

0.342

AC:

29466

AN:

86070

European-Finnish (FIN)

AF:

0.413

AC:

22036

AN:

53332

Middle Eastern (MID)

AF:

0.355

AC:

2047

AN:

5764

European-Non Finnish (NFE)

AF:

0.383

AC:

425599

AN:

1110500

Other (OTH)

AF:

0.362

AC:

21821

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

18176

36352

54528

72704

90880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13154

26308

39462

52616

65770

<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:

0.358

AC:

54414

AN:

151994

Hom.:

10159

Cov.:

AF XY:

0.357

AC XY:

26531

AN XY:

74256

show subpopulations

African (AFR)

AF:

0.291

AC:

12073

AN:

41448

American (AMR)

AF:

0.417

AC:

6368

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.361

AC:

1252

AN:

3472

East Asian (EAS)

AF:

0.207

AC:

1068

AN:

5156

South Asian (SAS)

AF:

0.335

AC:

1614

AN:

4818

European-Finnish (FIN)

AF:

0.414

AC:

4361

AN:

10540

Middle Eastern (MID)

AF:

0.289

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.389

AC:

26468

AN:

67972

Other (OTH)

AF:

0.352

AC:

741

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

1816

3632

5449

7265

9081

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

522

1044

1566

2088

2610

<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:

0.301

Hom.:

1255

Bravo

AF:

0.353

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

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

- -

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Deficiency of iodide peroxidase

Benign:2

Jan 12, 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

BayesDel_noAF

Benign

-0.98

CADD

Benign

0.012

(source)

DANN

Benign

0.31

PhyloP100

-3.7

PromoterAI

0.025

Neutral

(source)

Mutation Taster

=100/0

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