rs945006

Variant names:

• chr14-101562940-T-G
• rs945006
• NM_001362.4:c.*529T>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 21 publications found

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:20348): (DIO3 opposite strand upstream RNA) The mouse and human DIO3OS and DIO3 (MIM 601038) genes overlap and are transcribed in opposite directions. The mouse Dio3 gene is imprinted from the paternal allele during fetal development, suggesting that DIO3OS is a noncoding gene that may have a role in maintaining monoallelic expression of DIO3 (Hernandez et al., 2004 [PubMed 14962667]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
DIO3	NM_001362.4	c.*529T>G		3_prime_UTR_variant	Exon 1 of 1	ENST00000510508.5	NP_001353.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO3	ENST00000510508.5	c.*529T>G		3_prime_UTR_variant	Exon 1 of 1	6	NM_001362.4	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

African (AFR) AF: 0.250 AC: 3 AN: 12

American (AMR) AF: 0.0625 AC: 13 AN: 208

Ashkenazi Jewish (ASJ) AF: 0.0833 AC: 1 AN: 12

East Asian (EAS) AF: 0.00 AC: 0 AN: 30

South Asian (SAS) AF: 0.0500 AC: 3 AN: 60

European-Finnish (FIN) AF: 0.0730 AC: 1077 AN: 14746

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4

European-Non Finnish (NFE) AF: 0.0800 AC: 100 AN: 1250

Other (OTH) AF: 0.0774 AC: 13 AN: 168

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

African (AFR) AF: 0.457 AC: 18894 AN: 41350

American (AMR) AF: 0.125 AC: 1916 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0745 AC: 258 AN: 3464

East Asian (EAS) AF: 0.00739 AC: 38 AN: 5144

South Asian (SAS) AF: 0.0941 AC: 452 AN: 4802

European-Finnish (FIN) AF: 0.0715 AC: 750 AN: 10486

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.105 AC: 7153 AN: 67850

Other (OTH) AF: 0.143 AC: 301 AN: 2100

Alfa AF: 0.135 Hom.: 3886

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
PhyloP100		0.017
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs945006; hg19: chr14-102029277;