chr14-80203036-C-A

Variant names:

• chr14-80203036-C-A
• NM_013989.5:c.475G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_013989.5(DIO2):​c.475G>T​(p.Val159Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIO2 NM_013989.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.71
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013989.5. 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	NM_013989.5	MANE Select	c.475G>T	p.Val159Phe	missense	Exon 2 of 2	NP_054644.1	Q92813-1
	DIO2	NM_000793.6		c.475G>T	p.Val159Phe	missense	Exon 4 of 4	NP_000784.3
	DIO2	NM_001324462.2		c.475G>T	p.Val159Phe	missense	Exon 3 of 3	NP_001311391.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO2	ENST00000438257.9	TSL:1 MANE Select	c.475G>T	p.Val159Phe	missense	Exon 2 of 2	ENSP00000405854.5	Q92813-1
	DIO2	ENST00000556811.5	TSL:1	c.*276G>T		3_prime_UTR	Exon 3 of 3	ENSP00000451971.1	H0YJQ8
	DIO2	ENST00000555750.2	TSL:1	n.*313G>T		non_coding_transcript_exon	Exon 3 of 3	ENSP00000450980.2	A0A024R6J8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.62
BayesDel_addAF	Uncertain	0.017	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.047	D
MetaRNN	Uncertain	0.74	D
MetaSVM	Uncertain	0.31	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.9	D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
MutPred		0.55		Gain of catalytic residue at D162 (P = 2e-04)
MVP		0.76
MPC		1.0
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.79
Mutation Taster		=6/94	disease causing

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

Other links and lift over

hg19: chr14-80669379;