ENST00000497517.6:n.180+29641C>T

Variant names:

• chr2-1404043-C-T
• rs11675434
• ENST00000497517.6:n.180+29641C>T

Variant summary

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

The ENST00000497517.6(TPO):​n.180+29641C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.388 in 152,078 control chromosomes in the GnomAD database, including 11,702 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 0.39 (11702 hom., cov: 33)
• Consequence: TPO ENST00000497517.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.93
• Publications: 31 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=-1.0).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.476 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TPO	XM_047445652.1	c.-536C>T		5_prime_UTR_variant	Exon 2 of 19		XP_047301608.1
TPO	XM_047445653.1	c.-536C>T		5_prime_UTR_variant	Exon 2 of 19		XP_047301609.1
TPO	XM_047445654.1	c.-300C>T		5_prime_UTR_variant	Exon 2 of 18		XP_047301610.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TPO	ENST00000497517.6	n.180+29641C>T		intron_variant	Intron 1 of 5	1
TPO	ENST00000650224.1	n.378C>T		non_coding_transcript_exon_variant	Exon 2 of 4
ENSG00000231482	ENST00000650512.1	n.865+5486G>A		intron_variant	Intron 3 of 3

Frequencies

GnomAD3 genomes AF: 0.388 AC: 59013 AN: 151960 Hom.: 11690 Cov.: 33

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.349

Gnomad AMR AF: 0.484

Gnomad ASJ AF: 0.472

Gnomad EAS AF: 0.296

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.432

Gnomad MID AF: 0.361

Gnomad NFE AF: 0.412

Gnomad OTH AF: 0.383

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

GnomAD4 genome AF: 0.388 AC: 59058 AN: 152078 Hom.: 11702 Cov.: 33 AF XY: 0.389 AC XY: 28913 AN XY: 74328

African (AFR) AF: 0.301 AC: 12498 AN: 41488

American (AMR) AF: 0.485 AC: 7419 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.472 AC: 1639 AN: 3470

East Asian (EAS) AF: 0.296 AC: 1528 AN: 5162

South Asian (SAS) AF: 0.454 AC: 2191 AN: 4822

European-Finnish (FIN) AF: 0.432 AC: 4568 AN: 10562

Middle Eastern (MID) AF: 0.361 AC: 106 AN: 294

European-Non Finnish (NFE) AF: 0.412 AC: 27982 AN: 67964

Other (OTH) AF: 0.383 AC: 809 AN: 2112

Alfa AF: 0.399 Hom.: 39200

Bravo AF: 0.386

Asia WGS AF: 0.409 AC: 1421 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.090
DANN	Benign	0.70
PhyloP100		-1.9

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs11675434; hg19: chr2-1407815;