14-101562252-G-T

Variant names:

• chr14-101562252-G-T
• rs201390897
• ENST00000510508.5:c.756G>T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Strong BP6_Moderate BP7 BS2

The NM_001362.4(DIO3):​c.756G>T​(p.Ser252Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00244 in 1,612,726 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (8 hom.)
• Consequence: DIO3 NM_001362.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.24

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 Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 14-101562252-G-T is Benign according to our data. Variant chr14-101562252-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 3770502.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-101562252-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BS2: High AC in GnomAd4 at 237 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO3	NM_001362.4	c.756G>T	p.Ser252Ser	synonymous_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.756G>T	p.Ser252Ser	synonymous_variant	Exon 1 of 1	6		ENSP00000427336.3

Frequencies

GnomAD3 genomes AF: 0.00156 AC: 237 AN: 152222 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000772

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00273

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00122 AC: 302 AN: 248268 Hom.: 0 AF XY: 0.00115 AC XY: 155 AN XY: 134864

Gnomad AFR exome AF: 0.000775

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000557

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.000291

Gnomad NFE exome AF: 0.00210

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00253 AC: 3699 AN: 1460386 Hom.: 8 Cov.: 31 AF XY: 0.00244 AC XY: 1773 AN XY: 726570

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000927

Gnomad4 FIN exome AF: 0.000270

Gnomad4 NFE exome AF: 0.00313

Gnomad4 OTH exome AF: 0.00229

GnomAD4 genome AF: 0.00156 AC: 237 AN: 152340 Hom.: 0 Cov.: 33 AF XY: 0.00115 AC XY: 86 AN XY: 74494

Gnomad4 AFR AF: 0.000770

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000282

Gnomad4 NFE AF: 0.00273

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.00172

EpiCase AF: 0.00191

EpiControl AF: 0.00184

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DIO3: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	1.4
DANN	Benign	0.88

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: rs201390897; hg19: chr14-102028589;