rs732609

Positions:

Variant summary

Our verdict is Benign. Variant got -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. 15/20 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:7

Conservation

PhyloP100: 2.92

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 links:

(HGNC:):

links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1496155-A-C is described in Lovd as [Benign].

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/exons	MANE	UniProt
TPO	NM_001206744.2 linkuse as main transcript	c.2173A>C	p.Thr725Pro	missense_variant	12/17	ENST00000329066.9
LOC124905966	XR_007086185.1 linkuse as main transcript	n.167-9964T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9 linkuse as main transcript	c.2173A>C	p.Thr725Pro	missense_variant	12/17	1	NM_001206744.2	P1	P07202-1
	ENST00000650512.1 linkuse as main transcript	n.548-77694T>G		intron_variant, non_coding_transcript_variant

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

GnomAD3 exomes

AF:

0.429

AC:

107012

AN:

249642

Hom.:

23483

AF XY:

0.426

AC XY:

57487

AN XY:

134868

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 SAS exome

AF:

0.508

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

Gnomad4 AFR exome

AF:

0.625

Gnomad4 AMR exome

AF:

0.449

Gnomad4 ASJ exome

AF:

0.367

Gnomad4 EAS exome

AF:

0.451

Gnomad4 SAS exome

AF:

0.501

Gnomad4 FIN exome

AF:

0.412

Gnomad4 NFE exome

AF:

0.398

Gnomad4 OTH exome

AF:

0.427

GnomAD4 genome

AF:

0.468

AC:

71243

AN:

152130

Hom.:

17340

Cov.:

AF XY:

0.468

AC XY:

34844

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.607

Gnomad4 AMR

AF:

0.473

Gnomad4 ASJ

AF:

0.375

Gnomad4 EAS

AF:

0.418

Gnomad4 SAS

AF:

0.498

Gnomad4 FIN

AF:

0.420

Gnomad4 NFE

AF:

0.398

Gnomad4 OTH

AF:

0.470

Alfa

AF:

0.407

Hom.:

30918

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:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

Deficiency of iodide peroxidase

Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

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

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;.;.;.

MutationTaster

Benign

0.98

P;P;P;P;P;P;P

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over