ENST00000553979.1:n.179-50659G>A

Variant names:

• chr14-80308042-G-A
• rs10131076
• ENST00000553979.1:n.179-50659G>A

Variant summary

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

The ENST00000553979.1(DIO2-AS1):​n.179-50659G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.244 in 152,056 control chromosomes in the GnomAD database, including 7,752 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 0.24 (7752 hom., cov: 32)
• Consequence: DIO2-AS1 ENST00000553979.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0530
• Publications: 7 publications found

Genes affected

DIO2-AS1 (HGNC:44153): (DIO2 antisense RNA 1)

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

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.98).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO2-AS1	NR_038355.1	n.179-50659G>A		intron_variant	Intron 2 of 8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO2-AS1	ENST00000553979.1	n.179-50659G>A		intron_variant	Intron 2 of 8	1
DIO2	ENST00000554188.5	c.-325-29523C>T		intron_variant	Intron 1 of 3	4		ENSP00000451136.1
DIO2	ENST00000553594.1	c.-371+7732C>T		intron_variant	Intron 1 of 4	4		ENSP00000451265.1
DIO2	ENST00000556384.1	n.176+5427C>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.244 AC: 37069 AN: 151940 Hom.: 7722 Cov.: 32

Gnomad AFR AF: 0.567

Gnomad AMI AF: 0.0813

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0980

Gnomad EAS AF: 0.302

Gnomad SAS AF: 0.0707

Gnomad FIN AF: 0.154

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.202

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

GnomAD4 genome AF: 0.244 AC: 37158 AN: 152056 Hom.: 7752 Cov.: 32 AF XY: 0.241 AC XY: 17922 AN XY: 74338

African (AFR) AF: 0.567 AC: 23496 AN: 41420

American (AMR) AF: 0.115 AC: 1764 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0980 AC: 340 AN: 3468

East Asian (EAS) AF: 0.302 AC: 1562 AN: 5172

South Asian (SAS) AF: 0.0704 AC: 339 AN: 4818

European-Finnish (FIN) AF: 0.154 AC: 1624 AN: 10578

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.110 AC: 7495 AN: 67992

Other (OTH) AF: 0.200 AC: 423 AN: 2110

Alfa AF: 0.183 Hom.: 793

Bravo AF: 0.259

Asia WGS AF: 0.223 AC: 779 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.4
DANN	Benign	0.49
PhyloP100		-0.053

Splicing

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

Other links and lift over

dbSNP: rs10131076; hg19: chr14-80774385;