2-1434216-T-G

Variant names:

• chr2-1434216-T-G
• rs1514687
• NM_001206744.2:c.349+609T>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.349+609T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.858 in 151,790 control chromosomes in the GnomAD database, including 56,107 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 0.86 (56107 hom., cov: 33)
• Consequence: TPO NM_001206744.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.199
• Publications: 9 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=-0.99).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.912 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	NM_001206744.2	c.349+609T>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.349+609T>G		intron_variant	Intron 4 of 16	1	NM_001206744.2	ENSP00000329869.4

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130138 AN: 151672 Hom.: 56059 Cov.: 33

Gnomad AFR AF: 0.781

Gnomad AMI AF: 0.918

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 0.884

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.863

Gnomad MID AF: 0.826

Gnomad NFE AF: 0.882

Gnomad OTH AF: 0.863

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

GnomAD4 genome AF: 0.858 AC: 130243 AN: 151790 Hom.: 56107 Cov.: 33 AF XY: 0.861 AC XY: 63855 AN XY: 74160

African (AFR) AF: 0.781 AC: 32303 AN: 41338

American (AMR) AF: 0.912 AC: 13929 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 3112 AN: 3466

East Asian (EAS) AF: 0.883 AC: 4557 AN: 5158

South Asian (SAS) AF: 0.935 AC: 4505 AN: 4820

European-Finnish (FIN) AF: 0.863 AC: 9105 AN: 10550

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.882 AC: 59831 AN: 67870

Other (OTH) AF: 0.863 AC: 1820 AN: 2110

Alfa AF: 0.875 Hom.: 43282

Bravo AF: 0.858

Asia WGS AF: 0.914 AC: 3179 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.99
CADD	Benign	1.6
DANN	Benign	0.31
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1514687; hg19: chr2-1437988;