rs2280132

Variant names:

• chr2-1477383-G-T
• rs2280132
• NM_001206744.2:c.1117G>T

Variant summary

Our verdict is Benign. The variant received -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. 15/21 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:7
• Conservation: PhyloP100: 0.115
• Publications: 32 publications found

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: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

LALTOP (HGNC:58132):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 256605.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.475 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	NM_001206744.2	MANE Select	c.1117G>T	p.Ala373Ser	missense	Exon 8 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.1117G>T	p.Ala373Ser	missense	Exon 8 of 17	NP_000538.3
	TPO	NM_175721.3		c.1117G>T	p.Ala373Ser	missense	Exon 7 of 15	NP_783652.1	P07202-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TPO	ENST00000329066.9	TSL:1 MANE Select	c.1117G>T	p.Ala373Ser	missense	Exon 8 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.1117G>T	p.Ala373Ser	missense	Exon 8 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.1117G>T	p.Ala373Ser	missense	Exon 8 of 16	ENSP00000371636.3	P07202-2

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

GnomAD2 exomes AF: 0.470 AC: 61089 AN: 129864 AF XY: 0.466

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 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

African (AFR) AF: 0.352 AC: 10766 AN: 30588

American (AMR) AF: 0.489 AC: 17039 AN: 34878

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 11419 AN: 24600

East Asian (EAS) AF: 0.441 AC: 15596 AN: 35328

South Asian (SAS) AF: 0.386 AC: 30192 AN: 78154

European-Finnish (FIN) AF: 0.451 AC: 19106 AN: 42354

Middle Eastern (MID) AF: 0.448 AC: 1971 AN: 4404

European-Non Finnish (NFE) AF: 0.483 AC: 518487 AN: 1074384

Other (OTH) AF: 0.457 AC: 26168 AN: 57314

GnomAD4 genome AF: 0.435 AC: 66028 AN: 151930 Hom.: 14593 Cov.: 34 AF XY: 0.434 AC XY: 32238 AN XY: 74274

African (AFR) AF: 0.358 AC: 14855 AN: 41478

American (AMR) AF: 0.448 AC: 6837 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.435 AC: 1509 AN: 3470

East Asian (EAS) AF: 0.487 AC: 2492 AN: 5122

South Asian (SAS) AF: 0.371 AC: 1791 AN: 4830

European-Finnish (FIN) AF: 0.436 AC: 4610 AN: 10570

Middle Eastern (MID) AF: 0.424 AC: 123 AN: 290

European-Non Finnish (NFE) AF: 0.479 AC: 32506 AN: 67878

Other (OTH) AF: 0.410 AC: 864 AN: 2106

Alfa AF: 0.462 Hom.: 6414

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Deficiency of iodide peroxidase (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.027	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.000028	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-0.84	N
PhyloP100		0.12
PrimateAI	Uncertain	0.72	T
PROVEAN	Benign	0.47	N
REVEL	Benign	0.038
Sift	Benign	0.92	T
Sift4G	Benign	0.90	T
Polyphen		0.0050	B
Vest4		0.029
MPC		1.1
ClinPred		0.0033	T
GERP RS		-1.3
Varity_R		0.053
gMVP		0.22
Mutation Taster		=98/2	polymorphism (auto)

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

Other links and lift over

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