14-80200883-A-T

Variant names:

• chr14-80200883-A-T
• rs225017
• NM_013989.5:c.*1806T>A

Variant summary

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

The NM_013989.5(DIO2):​c.*1806T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.578 in 151,944 control chromosomes in the GnomAD database, including 28,067 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 0.58 (28067 hom., cov: 32)
  • Failed GnomAD Quality Control
• Consequence: DIO2 NM_013989.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0580

Genes affected

DIO2 (HGNC:2884): (iodothyronine deiodinase 2) The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the conversion of prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4) to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by outer ring 5'-deiodination. This gene is widely expressed, including in thyroid and brain. It is thought to be responsible for the 'local' production of T3, and thus important in influencing thyroid hormone action in these tissues. It has also been reported to be highly expressed in thyroids of patients with Graves disease, and in follicular adenomas. The intrathyroidal T4 to T3 conversion by this enzyme may contribute significantly to the relative increase in thyroidal T3 production in these patients. This protein is a selenoprotein containing the non-standard amino acid, selenocysteine (Sec), which is encoded by the UGA codon that 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. Unlike the other two members (DIO1 and DIO3) of this enzyme family, the mRNA for this gene contains an additional in-frame UGA codon that has been reported (in human) to function either as a Sec or a stop codon, which can result in two isoforms with one or two Sec residues; however, only the upstream Sec (conserved with the single Sec residue found at the active site in DIO1 and DIO3) was shown to be essential for enzyme activity (PMID:10403186). Alternatively spliced transcript variants have been described for this gene. [provided by RefSeq, Oct 2018]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.847 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO2	NM_013989.5	c.*1806T>A		3_prime_UTR_variant	Exon 2 of 2	ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257	c.*1806T>A		3_prime_UTR_variant	Exon 2 of 2	1	NM_013989.5	ENSP00000405854.5
DIO2	ENST00000557010	c.*1806T>A		3_prime_UTR_variant	Exon 4 of 4	2		ENSP00000451419.1

Frequencies

GnomAD3 genomes AF: 0.578 AC: 87681 AN: 151826 Hom.: 27994 Cov.: 32

Gnomad AFR AF: 0.854

Gnomad AMI AF: 0.409

Gnomad AMR AF: 0.553

Gnomad ASJ AF: 0.500

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.579

Gnomad FIN AF: 0.384

Gnomad MID AF: 0.399

Gnomad NFE AF: 0.440

Gnomad OTH AF: 0.544

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

GnomAD4 genome AF: 0.578 AC: 87815 AN: 151944 Hom.: 28067 Cov.: 32 AF XY: 0.576 AC XY: 42782 AN XY: 74234

Gnomad4 AFR AF: 0.855

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.500

Gnomad4 EAS AF: 0.741

Gnomad4 SAS AF: 0.578

Gnomad4 FIN AF: 0.384

Gnomad4 NFE AF: 0.440

Gnomad4 OTH AF: 0.544

Alfa AF: 0.500 Hom.: 2801

Bravo AF: 0.606

Asia WGS AF: 0.695 AC: 2410 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs225017; hg19: chr14-80667226;