rs2175977

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.1193G>C(p.Ser398Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.622 in 1,525,816 control chromosomes in the GnomAD database, including 297,044 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.66 ( 33425 hom., cov: 35)

Exomes 𝑓: 0.62 ( 263619 hom. )

Consequence

TPO
NM_001206744.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 1.05

Publications

37 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=1.0097892E-6).

BP6

Variant 2-1477459-G-C is Benign according to our data. Variant chr2-1477459-G-C is described in ClinVar as Benign. ClinVar VariationId is 256606.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.781 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206744.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPO	NM_001206744.2	MANE Select	c.1193G>C	p.Ser398Thr	missense	Exon 8 of 17	NP_001193673.1
TPO	NM_000547.6		c.1193G>C	p.Ser398Thr	missense	Exon 8 of 17	NP_000538.3
TPO	NM_175721.3		c.1193G>C	p.Ser398Thr	missense	Exon 7 of 15	NP_783652.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TPO	ENST00000329066.9	TSL:1 MANE Select	c.1193G>C	p.Ser398Thr	missense	Exon 8 of 17	ENSP00000329869.4
TPO	ENST00000345913.8	TSL:1	c.1193G>C	p.Ser398Thr	missense	Exon 8 of 17	ENSP00000318820.7
TPO	ENST00000382201.7	TSL:1	c.1193G>C	p.Ser398Thr	missense	Exon 8 of 16	ENSP00000371636.3

Frequencies

GnomAD3 genomes

AF:

0.657

AC:

99771

AN:

151964

Hom.:

33392

Cov.:

show subpopulations

Gnomad AFR

AF:

0.788

Gnomad AMI

AF:

0.547

Gnomad AMR

AF:

0.610

Gnomad ASJ

AF:

0.551

Gnomad EAS

AF:

0.772

Gnomad SAS

AF:

0.647

Gnomad FIN

AF:

0.549

Gnomad MID

AF:

0.678

Gnomad NFE

AF:

0.603

Gnomad OTH

AF:

0.637

GnomAD2 exomes

AF:

0.639

AC:

77787

AN:

121698

AF XY:

0.636

show subpopulations

Gnomad AFR exome

AF:

0.826

Gnomad AMR exome

AF:

0.650

Gnomad ASJ exome

AF:

0.573

Gnomad EAS exome

AF:

0.790

Gnomad FIN exome

AF:

0.549

Gnomad NFE exome

AF:

0.614

Gnomad OTH exome

AF:

0.611

GnomAD4 exome

AF:

0.618

AC:

848771

AN:

1373744

Hom.:

263619

Cov.:

114

AF XY:

0.618

AC XY:

418908

AN XY:

677872

show subpopulations

African (AFR)

AF:

0.797

AC:

23557

AN:

29540

American (AMR)

AF:

0.644

AC:

22552

AN:

35002

Ashkenazi Jewish (ASJ)

AF:

0.566

AC:

14016

AN:

24746

East Asian (EAS)

AF:

0.755

AC:

26180

AN:

34672

South Asian (SAS)

AF:

0.638

AC:

50024

AN:

78448

European-Finnish (FIN)

AF:

0.558

AC:

19984

AN:

35830

Middle Eastern (MID)

AF:

0.631

AC:

2640

AN:

4186

European-Non Finnish (NFE)

AF:

0.609

AC:

654237

AN:

1074132

Other (OTH)

AF:

0.622

AC:

35581

AN:

57188

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

21938

43876

65815

87753

109691

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18128

36256

54384

72512

90640

<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:

0.657

AC:

99851

AN:

152072

Hom.:

33425

Cov.:

AF XY:

0.655

AC XY:

48679

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.788

AC:

32720

AN:

41518

American (AMR)

AF:

0.610

AC:

9329

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.551

AC:

1907

AN:

3464

East Asian (EAS)

AF:

0.772

AC:

3973

AN:

5146

South Asian (SAS)

AF:

0.648

AC:

3128

AN:

4830

European-Finnish (FIN)

AF:

0.549

AC:

5813

AN:

10580

Middle Eastern (MID)

AF:

0.671

AC:

196

AN:

292

European-Non Finnish (NFE)

AF:

0.603

AC:

40947

AN:

67938

Other (OTH)

AF:

0.636

AC:

1340

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1755

3511

5266

7022

8777

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

802

1604

2406

3208

4010

<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:

0.621

Hom.:

6058

Bravo

AF:

0.669

TwinsUK

AF:

0.607

AC:

2250

ALSPAC

AF:

0.608

AC:

2344

ESP6500AA

AF:

0.864

AC:

2498

ESP6500EA

AF:

0.740

AC:

4199

ExAC

AF:

0.469

AC:

22060

Asia WGS

AF:

0.679

AC:

2355

AN:

3466

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Deficiency of iodide peroxidase (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.52

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.53

MetaRNN

Benign

0.0000010

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.3

PhyloP100

1.0

PrimateAI

Uncertain

0.76

PROVEAN

Benign

-2.1

REVEL

Benign

0.26

Sift

Benign

0.15

Sift4G

Benign

0.14

Polyphen

1.0

Vest4

0.036

MPC

1.8

ClinPred

0.034

GERP RS

4.1

Varity_R

0.28

gMVP

0.64

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over