14-101561543-G-T

Variant names:

• chr14-101561543-G-T
• ENST00000510508.5:c.47G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001362.4(DIO3):​c.47G>T​(p.Gly16Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,586 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DIO3 NM_001362.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.93

Genes affected

DIO3 (HGNC:2885): (iodothyronine deiodinase 3) The protein encoded by this intronless gene belongs to the iodothyronine deiodinase family. It catalyzes the inactivation of thyroid hormone by inner ring deiodination of the prohormone thyroxine (T4) and the bioactive hormone 3,3',5-triiodothyronine (T3) to inactive metabolites, 3,3',5'-triiodothyronine (RT3) and 3,3'-diiodothyronine (T2), respectively. This enzyme is highly expressed in pregnant uterus, placenta, fetal and neonatal tissues, and thought to prevent premature exposure of developing fetal tissues to adult levels of thyroid hormones. It regulates circulating fetal thyroid hormone concentrations, and thus plays a critical role in mammalian development. Knockout mice lacking this gene exhibit abnormalities related to development and reproduction, and increased activity of this enzyme in infants with hemangiomas causes severe hypothyroidism. This protein is a selenoprotein, containing the rare selenocysteine (Sec) amino acid at its active site. Sec is encoded by the UGA codon, which 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. [provided by RefSeq, May 2016]

DIO3OS (HGNC:20348): (DIO3 opposite strand upstream RNA) The mouse and human DIO3OS and DIO3 (MIM 601038) genes overlap and are transcribed in opposite directions. The mouse Dio3 gene is imprinted from the paternal allele during fetal development, suggesting that DIO3OS is a noncoding gene that may have a role in maintaining monoallelic expression of DIO3 (Hernandez et al., 2004 [PubMed 14962667]).[supplied by OMIM, Mar 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15324944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO3	NM_001362.4	c.47G>T	p.Gly16Val	missense_variant	Exon 1 of 1		NP_001353.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO3	ENST00000510508.5	c.47G>T	p.Gly16Val	missense_variant	Exon 1 of 1	6		ENSP00000427336.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459586 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.47G>T (p.G16V) alteration is located in exon 1 (coding exon 1) of the DIO3 gene. This alteration results from a G to T substitution at nucleotide position 47, causing the glycine (G) at amino acid position 16 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.14
Eigen_PC	Benign	-0.20
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.52	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.34	N
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.62	N
REVEL	Benign	0.022
Sift	Uncertain	0.011	D
Sift4G	Benign	0.081	T
Vest4		0.16
MutPred		0.28		Gain of catalytic residue at G19 (P = 2e-04);
MVP		0.40
MPC		1.2
ClinPred		0.55	D
GERP RS		2.7
Varity_R		0.13

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-102027880;