2-1456232-G-T

Position:

chr2-1456232-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.769G>T(p.Ala257Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.381 in 1,613,664 control chromosomes in the GnomAD database, including 118,663 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 0.38 ( 11234 hom., cov: 34)

Exomes 𝑓: 0.38 ( 107429 hom. )

Consequence

TPO
NM_001206744.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.754

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:

ENSG00000231482 (HGNC:):

ENSG00000231482 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=2.718866E-4).

BP6

Variant 2-1456232-G-T is Benign according to our data. Variant chr2-1456232-G-T is described in ClinVar as [Benign]. Clinvar id is 256616.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-1456232-G-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TPO	NM_001206744.2 link	c.769G>T	p.Ala257Ser	missense_variant	7/17	ENST00000329066.9	NP_001193673.1	P07202-1Q502Y3Q6P534

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9 link	c.769G>T	p.Ala257Ser	missense_variant	7/17	1	NM_001206744.2	ENSP00000329869.4		P07202-1

Frequencies

GnomAD3 genomes

AF:

0.382

AC:

57959

AN:

151874

Hom.:

11217

Cov.:

show subpopulations

Gnomad AFR

AF:

0.369

Gnomad AMI

AF:

0.393

Gnomad AMR

AF:

0.414

Gnomad ASJ

AF:

0.397

Gnomad EAS

AF:

0.184

Gnomad SAS

AF:

0.483

Gnomad FIN

AF:

0.433

Gnomad MID

AF:

0.290

Gnomad NFE

AF:

0.381

Gnomad OTH

AF:

0.387

GnomAD3 exomes

AF:

0.381

AC:

95673

AN:

251118

Hom.:

18767

AF XY:

0.386

AC XY:

52328

AN XY:

135740

show subpopulations

Gnomad AFR exome

AF:

0.372

Gnomad AMR exome

AF:

0.383

Gnomad ASJ exome

AF:

0.396

Gnomad EAS exome

AF:

0.180

Gnomad SAS exome

AF:

0.491

Gnomad FIN exome

AF:

0.427

Gnomad NFE exome

AF:

0.374

Gnomad OTH exome

AF:

0.387

GnomAD4 exome

AF:

0.380

AC:

556027

AN:

1461672

Hom.:

107429

Cov.:

AF XY:

0.383

AC XY:

278506

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.376

Gnomad4 AMR exome

AF:

0.387

Gnomad4 ASJ exome

AF:

0.394

Gnomad4 EAS exome

AF:

0.195

Gnomad4 SAS exome

AF:

0.484

Gnomad4 FIN exome

AF:

0.422

Gnomad4 NFE exome

AF:

0.377

Gnomad4 OTH exome

AF:

0.381

GnomAD4 genome

AF:

0.382

AC:

58021

AN:

151992

Hom.:

11234

Cov.:

AF XY:

0.385

AC XY:

28610

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.369

Gnomad4 AMR

AF:

0.414

Gnomad4 ASJ

AF:

0.397

Gnomad4 EAS

AF:

0.184

Gnomad4 SAS

AF:

0.482

Gnomad4 FIN

AF:

0.433

Gnomad4 NFE

AF:

0.381

Gnomad4 OTH

AF:

0.385

Alfa

AF:

0.373

Hom.:

19656

Bravo

AF:

0.375

TwinsUK

AF:

0.381

AC:

1412

ALSPAC

AF:

0.376

AC:

1451

ESP6500AA

AF:

0.376

AC:

1657

ESP6500EA

AF:

0.384

AC:

3302

ExAC

AF:

0.379

AC:

46038

Asia WGS

AF:

0.364

AC:

1267

AN:

3478

EpiCase

AF:

0.376

EpiControl

AF:

0.377

ClinVar

Significance: Benign

Submissions summary: Benign:8

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	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 12, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

6.8

DANN

Benign

0.97

DEOGEN2

Benign

0.36

T;T;.;.;.;.

Eigen

Benign

-0.72

Eigen_PC

Benign

-0.81

FATHMM_MKL

Benign

0.10

LIST_S2

Benign

0.41

T;.;T;T;T;T

MetaRNN

Benign

0.00027

T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

L;L;L;L;L;.

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.6

N;N;N;N;N;N

REVEL

Benign

0.069

Sift

Benign

0.052

T;T;T;D;T;T

Sift4G

Uncertain

0.044

D;D;T;T;T;T

Polyphen

0.056

B;B;B;P;P;.

Vest4

0.069

MPC

0.19

ClinPred

0.0088

GERP RS

0.49

Varity_R

0.14

gMVP

0.41

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