rs945006

Positions:

• chr14-101562940-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001362.4(DIO3):​c.*529T>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.185 in 168,168 control chromosomes in the GnomAD database, including 4,974 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 0.20 (4918 hom., cov: 32)
  • Exomes 𝑓: 0.073 (56 hom.)
• Consequence: DIO3 NM_001362.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0170

Genes affected

DIO3 (HGNC:2885): (iodothyronine deiodinase 3) The protein encoded by this intronless gene belongs to the iodothyronine deiodinase family. It catalyzes the inactivation of thyroid hormone by inner ring deiodination of the prohormone thyroxine (T4) and the bioactive hormone 3,3',5-triiodothyronine (T3) to inactive metabolites, 3,3',5'-triiodothyronine (RT3) and 3,3'-diiodothyronine (T2), respectively. This enzyme is highly expressed in pregnant uterus, placenta, fetal and neonatal tissues, and thought to prevent premature exposure of developing fetal tissues to adult levels of thyroid hormones. It regulates circulating fetal thyroid hormone concentrations, and thus plays a critical role in mammalian development. Knockout mice lacking this gene exhibit abnormalities related to development and reproduction, and increased activity of this enzyme in infants with hemangiomas causes severe hypothyroidism. This protein is a selenoprotein, containing the rare selenocysteine (Sec) amino acid at its active site. Sec is encoded by the UGA codon, which normally signals translation termination. The 3' UTRs of selenoprotein mRNAs contain a conserved stem-loop structure, designated the Sec insertion sequence (SECIS) element, that is necessary for the recognition of UGA as a Sec codon rather than as a stop signal. [provided by RefSeq, May 2016]

DIO3OS (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO3	NM_001362.4	c.*529T>G		3_prime_UTR_variant	1/1		NP_001353.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO3	ENST00000510508.5	c.*529T>G		3_prime_UTR_variant	1/1	6		ENSP00000427336.3

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29774 AN: 151562 Hom.: 4905 Cov.: 32

Gnomad AFR AF: 0.457

Gnomad AMI AF: 0.0474

Gnomad AMR AF: 0.125

Gnomad ASJ AF: 0.0745

Gnomad EAS AF: 0.00717

Gnomad SAS AF: 0.0945

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.101

Gnomad NFE AF: 0.105

Gnomad OTH AF: 0.144

GnomAD4 exome AF: 0.0734 AC: 1210 AN: 16490 Hom.: 56 Cov.: 0 AF XY: 0.0708 AC XY: 554 AN XY: 7828

Gnomad4 AFR exome AF: 0.250

Gnomad4 AMR exome AF: 0.0625

Gnomad4 ASJ exome AF: 0.0833

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0500

Gnomad4 FIN exome AF: 0.0730

Gnomad4 NFE exome AF: 0.0800

Gnomad4 OTH exome AF: 0.0774

GnomAD4 genome AF: 0.197 AC: 29838 AN: 151678 Hom.: 4918 Cov.: 32 AF XY: 0.188 AC XY: 13936 AN XY: 74130

Gnomad4 AFR AF: 0.457

Gnomad4 AMR AF: 0.125

Gnomad4 ASJ AF: 0.0745

Gnomad4 EAS AF: 0.00739

Gnomad4 SAS AF: 0.0941

Gnomad4 FIN AF: 0.0715

Gnomad4 NFE AF: 0.105

Gnomad4 OTH AF: 0.143

Alfa AF: 0.127 Hom.: 2622

Bravo AF: 0.211

Asia WGS AF: 0.0780 AC: 271 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	12
DANN	Benign	0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs945006; hg19: chr14-102029277;