14-80338614-T-C

Variant names:

• chr14-80338614-T-C
• rs10483948
• ENST00000553979.1:n.179-20087T>C

Variant summary

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

The ENST00000554188.5(DIO2):​c.-326+49064A>G variant causes a intron 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 ENST00000554188.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.949
• Publications: 4 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.875 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000554188.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO2-AS1	NR_038355.1		n.179-20087T>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO2-AS1	ENST00000553979.1	TSL:1	n.179-20087T>C		intron	N/A
	DIO2	ENST00000554188.5	TSL:4	c.-326+49064A>G		intron	N/A	ENSP00000451136.1	G3V3A8

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

African (AFR) AF: 0.882 AC: 36646 AN: 41536

American (AMR) AF: 0.664 AC: 10148 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.656 AC: 2276 AN: 3470

East Asian (EAS) AF: 0.607 AC: 3130 AN: 5160

South Asian (SAS) AF: 0.597 AC: 2876 AN: 4818

European-Finnish (FIN) AF: 0.757 AC: 8017 AN: 10584

Middle Eastern (MID) AF: 0.729 AC: 213 AN: 292

European-Non Finnish (NFE) AF: 0.702 AC: 47766 AN: 67998

Other (OTH) AF: 0.710 AC: 1498 AN: 2110

Alfa AF: 0.663 Hom.: 3686

Bravo AF: 0.741

Asia WGS AF: 0.615 AC: 2143 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.90
DANN	Benign	0.29
PhyloP100		-0.95

Splicing

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

Other links and lift over

dbSNP: rs10483948; hg19: chr14-80804957;