rs1514685

Variant names:

• chr2-1435493-T-G
• rs1514685
• NM_001206744.2:c.350-759T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206744.2(TPO):​c.350-759T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.315 in 152,052 control chromosomes in the GnomAD database, including 8,277 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8277 hom., cov: 33)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.06
• Publications: 3 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: Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000231482 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.468 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2	c.350-759T>G		intron_variant	Intron 4 of 16	ENST00000329066.9	NP_001193673.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000329066.9	c.350-759T>G		intron_variant	Intron 4 of 16	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.315 AC: 47810 AN: 151934 Hom.: 8239 Cov.: 33

Gnomad AFR AF: 0.426

Gnomad AMI AF: 0.175

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.295

Gnomad EAS AF: 0.262

Gnomad SAS AF: 0.484

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.232

Gnomad OTH AF: 0.325

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.315 AC: 47907 AN: 152052 Hom.: 8277 Cov.: 33 AF XY: 0.321 AC XY: 23878 AN XY: 74328

African (AFR) AF: 0.426 AC: 17665 AN: 41446

American (AMR) AF: 0.397 AC: 6062 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 1022 AN: 3468

East Asian (EAS) AF: 0.261 AC: 1352 AN: 5182

South Asian (SAS) AF: 0.484 AC: 2327 AN: 4808

European-Finnish (FIN) AF: 0.265 AC: 2798 AN: 10574

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.232 AC: 15749 AN: 67978

Other (OTH) AF: 0.329 AC: 695 AN: 2112

Alfa AF: 0.287 Hom.: 1099

Bravo AF: 0.323

Asia WGS AF: 0.416 AC: 1445 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.0020
DANN	Benign	0.48
PhyloP100		-1.1
Mutation Taster		=100/0	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: rs1514685; hg19: chr2-1439265;