14-80201236-G-A

Position:

• chr14-80201236-G-A

Variant summary

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

The ENST00000438257.9(DIO2):​c.*1453C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 151,660 control chromosomes in the GnomAD database, including 11,035 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as other (no stars).

• Frequency:
  • Genomes: 𝑓 0.38 (11035 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: DIO2 ENST00000438257.9 3_prime_UTR
• Clinical Significance: other no assertion criteria provided O:1
• Conservation: PhyloP100: 0.349

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=-0.94).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO2	NM_013989.5	c.*1453C>T		3_prime_UTR_variant	2/2	ENST00000438257.9	NP_054644.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO2	ENST00000438257.9	c.*1453C>T		3_prime_UTR_variant	2/2	1	NM_013989.5	ENSP00000405854	P1
DIO2	ENST00000557010.5	c.*1453C>T		3_prime_UTR_variant	4/4	2		ENSP00000451419	P1

Frequencies

GnomAD3 genomes AF: 0.375 AC: 56848 AN: 151548 Hom.: 11014 Cov.: 32

Gnomad AFR AF: 0.432

Gnomad AMI AF: 0.324

Gnomad AMR AF: 0.455

Gnomad ASJ AF: 0.401

Gnomad EAS AF: 0.431

Gnomad SAS AF: 0.475

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.283

Gnomad NFE AF: 0.331

Gnomad OTH AF: 0.368

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 ASJ exome AF: 0.00

GnomAD4 genome AF: 0.375 AC: 56915 AN: 151660 Hom.: 11035 Cov.: 32 AF XY: 0.375 AC XY: 27817 AN XY: 74088

Gnomad4 AFR AF: 0.432

Gnomad4 AMR AF: 0.456

Gnomad4 ASJ AF: 0.401

Gnomad4 EAS AF: 0.430

Gnomad4 SAS AF: 0.475

Gnomad4 FIN AF: 0.245

Gnomad4 NFE AF: 0.331

Gnomad4 OTH AF: 0.370

Alfa AF: 0.342 Hom.: 8308

Bravo AF: 0.393

Asia WGS AF: 0.460 AC: 1598 AN: 3478

ClinVar

Significance: other

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Levothyroxine response Other:1

other, no assertion criteria provided

research

Pharmacogenomics/Precision medicine lab, University of Petra

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- This SNP was not associated with any of thyroid panel hormones in the study

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.2
DANN	Benign	0.47

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: rs225015; hg19: chr14-80667579;