rs2280132

Positions:

chr2-1477383-G-T

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as 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

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:

TPO (HGNC:):

TPO 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=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 id is 256605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1477383-G-T is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
TPO	NM_001206744.2 linkuse as main transcript	c.1117G>T	p.Ala373Ser	missense_variant	8/17	ENST00000329066.9	NP_001193673.1	P07202-1Q502Y3Q6P534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9 linkuse as main transcript	c.1117G>T	p.Ala373Ser	missense_variant	8/17	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

GnomAD3 exomes

AF:

0.470

AC:

61089

AN:

129864

Hom.:

14411

AF XY:

0.466

AC XY:

33103

AN XY:

71104

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 SAS exome

AF:

0.390

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

Gnomad4 AFR exome

AF:

0.352

Gnomad4 AMR exome

AF:

0.489

Gnomad4 ASJ exome

AF:

0.464

Gnomad4 EAS exome

AF:

0.441

Gnomad4 SAS exome

AF:

0.386

Gnomad4 FIN exome

AF:

0.451

Gnomad4 NFE exome

AF:

0.483

Gnomad4 OTH exome

AF:

0.457

GnomAD4 genome

AF:

0.435

AC:

66028

AN:

151930

Hom.:

14593

Cov.:

AF XY:

0.434

AC XY:

32238

AN XY:

74274

show subpopulations

Gnomad4 AFR

AF:

0.358

Gnomad4 AMR

AF:

0.448

Gnomad4 ASJ

AF:

0.435

Gnomad4 EAS

AF:

0.487

Gnomad4 SAS

AF:

0.371

Gnomad4 FIN

AF:

0.436

Gnomad4 NFE

AF:

0.479

Gnomad4 OTH

AF:

0.410

Alfa

AF:

0.465

Hom.:

3749

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

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

Deficiency of iodide peroxidase

Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

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

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;.

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

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