rs2280132

chr2-1477383-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 (★★). Synonymous variant affecting the same amino acid position (i.e. A373A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (14593 hom., cov: 34)
  • Exomes 𝑓: 0.47 (154082 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.115

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]

(HGNC:):

ACMG classification

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	UniProt
TPO	NM_001206744.2	c.1117G>T	p.Ala373Ser	missense_variant	8/17	ENST00000329066.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TPO	ENST00000329066.9	c.1117G>T	p.Ala373Ser	missense_variant	8/17	1	NM_001206744.2	P1
	ENST00000650512.1	n.548-58922C>A		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes AF: 0.435 AC: 66004 AN: 151822 Hom.: 14587 Cov.: 34

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

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.: 95 AF XY: 0.469 AC XY: 319384 AN XY: 681332

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.: 34 AF XY: 0.434 AC XY: 32238 AN XY: 74274

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Deficiency of iodide peroxidase Benign:2

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	0.081
BayesDel_addAF	Benign	-0.71	T
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	N
LIST_S2	Benign	0.49	T;.;T;T;T
MetaRNN	Benign	0.000028	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.84	N;N;N;N;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P
PrimateAI	Uncertain	0.72	T
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	T
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

Other links and lift over

dbSNP: rs2280132; hg19: chr2-1481155; COSMIC: COSV61093726;