rs1126799

Variant names:

• chr2-1516904-T-C
• rs1126799
• NM_001206744.2:c.2540T>C

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.2540T>C​(p.Val847Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.56 in 1,613,542 control chromosomes in the GnomAD database, including 256,715 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V847M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.62 (30292 hom., cov: 33)
  • Exomes 𝑓: 0.55 (226423 hom.)
• Consequence: TPO NM_001206744.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.630
• Publications: 39 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=2.9479213E-6).
• BP6: Variant 2-1516904-T-C is Benign according to our data. Variant chr2-1516904-T-C is described in ClinVar as Benign. ClinVar VariationId is 256614.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.772 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.2540T>C	p.Val847Ala	missense	Exon 15 of 17	NP_001193673.1	P07202-1
	TPO	NM_000547.6		c.2540T>C	p.Val847Ala	missense	Exon 15 of 17	NP_000538.3
	TPO	NM_175721.3		c.2408T>C	p.Val803Ala	missense	Exon 13 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.2540T>C	p.Val847Ala	missense	Exon 15 of 17	ENSP00000329869.4	P07202-1
	TPO	ENST00000345913.8	TSL:1	c.2540T>C	p.Val847Ala	missense	Exon 15 of 17	ENSP00000318820.7	P07202-1
	TPO	ENST00000382201.7	TSL:1	c.2369T>C	p.Val790Ala	missense	Exon 14 of 16	ENSP00000371636.3	P07202-2

Frequencies

GnomAD3 genomes AF: 0.622 AC: 94584 AN: 151998 Hom.: 30241 Cov.: 33

Gnomad AFR AF: 0.778

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.613

Gnomad ASJ AF: 0.505

Gnomad EAS AF: 0.597

Gnomad SAS AF: 0.656

Gnomad FIN AF: 0.613

Gnomad MID AF: 0.506

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.586

GnomAD2 exomes AF: 0.587 AC: 147233 AN: 250810 AF XY: 0.583

Gnomad AFR exome AF: 0.783

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.480

Gnomad EAS exome AF: 0.587

Gnomad FIN exome AF: 0.609

Gnomad NFE exome AF: 0.537

Gnomad OTH exome AF: 0.551

GnomAD4 exome AF: 0.554 AC: 808956 AN: 1461426 Hom.: 226423 Cov.: 62 AF XY: 0.555 AC XY: 403796 AN XY: 727020

African (AFR) AF: 0.791 AC: 26480 AN: 33478

American (AMR) AF: 0.619 AC: 27685 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.485 AC: 12685 AN: 26136

East Asian (EAS) AF: 0.623 AC: 24739 AN: 39698

South Asian (SAS) AF: 0.651 AC: 56113 AN: 86252

European-Finnish (FIN) AF: 0.602 AC: 31947 AN: 53078

Middle Eastern (MID) AF: 0.479 AC: 2760 AN: 5762

European-Non Finnish (NFE) AF: 0.533 AC: 592487 AN: 1111916

Other (OTH) AF: 0.564 AC: 34060 AN: 60388

GnomAD4 genome AF: 0.623 AC: 94699 AN: 152116 Hom.: 30292 Cov.: 33 AF XY: 0.624 AC XY: 46406 AN XY: 74370

African (AFR) AF: 0.779 AC: 32323 AN: 41506

American (AMR) AF: 0.613 AC: 9368 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.505 AC: 1750 AN: 3468

East Asian (EAS) AF: 0.598 AC: 3078 AN: 5150

South Asian (SAS) AF: 0.656 AC: 3168 AN: 4832

European-Finnish (FIN) AF: 0.613 AC: 6492 AN: 10584

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.539 AC: 36656 AN: 67986

Other (OTH) AF: 0.587 AC: 1239 AN: 2110

Alfa AF: 0.559 Hom.: 101228

Bravo AF: 0.626

TwinsUK AF: 0.519 AC: 1923

ALSPAC AF: 0.526 AC: 2028

ESP6500AA AF: 0.771 AC: 3398

ESP6500EA AF: 0.532 AC: 4578

ExAC AF: 0.589 AC: 71519

Asia WGS AF: 0.655 AC: 2276 AN: 3478

EpiCase AF: 0.527

EpiControl AF: 0.522

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.54	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.6
DANN	Benign	0.19
DEOGEN2	Benign	0.26	T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.0011	N
LIST_S2	Benign	0.28	T
MetaRNN	Benign	0.0000030	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
PhyloP100		0.63
PrimateAI	Benign	0.41	T
PROVEAN	Benign	1.7	N
REVEL	Uncertain	0.32
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.036
MPC		0.19
ClinPred		0.011	T
GERP RS		4.6
Varity_R		0.033
gMVP		0.59
Mutation Taster		=99/1	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: rs1126799; hg19: chr2-1520676; COSMIC: COSV61097695;