14-80338614-T-C

Position:

• chr14-80338614-T-C

Variant summary

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

The NR_038355.1(DIO2-AS1):​n.179-20087T>C variant causes a intron, non coding transcript change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.745 in 152,156 control chromosomes in the GnomAD database, including 42,975 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 0.75 (42975 hom., cov: 32)
• Consequence: DIO2-AS1 NR_038355.1 intron, non_coding_transcript
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.949

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

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 = 0.875 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO2-AS1	NR_038355.1	n.179-20087T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO2-AS1	ENST00000553979.1	n.179-20087T>C		intron_variant, non_coding_transcript_variant		1
DIO2	ENST00000554188.5	c.-326+49064A>G		intron_variant		4		ENSP00000451136

Frequencies

GnomAD3 genomes AF: 0.745 AC: 113280 AN: 152038 Hom.: 42933 Cov.: 32

Gnomad AFR AF: 0.882

Gnomad AMI AF: 0.877

Gnomad AMR AF: 0.665

Gnomad ASJ AF: 0.656

Gnomad EAS AF: 0.607

Gnomad SAS AF: 0.597

Gnomad FIN AF: 0.757

Gnomad MID AF: 0.726

Gnomad NFE AF: 0.702

Gnomad OTH AF: 0.718

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

GnomAD4 genome AF: 0.745 AC: 113370 AN: 152156 Hom.: 42975 Cov.: 32 AF XY: 0.744 AC XY: 55323 AN XY: 74368

Gnomad4 AFR AF: 0.882

Gnomad4 AMR AF: 0.664

Gnomad4 ASJ AF: 0.656

Gnomad4 EAS AF: 0.607

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.757

Gnomad4 NFE AF: 0.702

Gnomad4 OTH AF: 0.710

Alfa AF: 0.653 Hom.: 3391

Bravo AF: 0.741

Asia WGS AF: 0.615 AC: 2143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.90
DANN	Benign	0.29

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs10483948; hg19: chr14-80804957;