14-101561531-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001362.4(DIO3):c.35G>A(p.Gly12Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00453 in 1,609,926 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0029 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0047 ( 29 hom. )

Consequence

DIO3
NM_001362.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 3.77

Variant links:

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]

DIO3 links:

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]

DIO3OS links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0053586066).

BP6

Variant 14-101561531-G-A is Benign according to our data. Variant chr14-101561531-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3770501.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr14-101561531-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 448 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO3	NM_001362.4 link	c.35G>A	p.Gly12Glu	missense_variant	Exon 1 of 1		NP_001353.4	P55073Q86TU3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO3	ENST00000510508.5 link	c.35G>A	p.Gly12Glu	missense_variant	Exon 1 of 1	6		ENSP00000427336.3		P55073

Frequencies

GnomAD3 genomes

AF:

0.00294

AC:

448

AN:

152170

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00111

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00137

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00179

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00519

Gnomad OTH

AF:

0.00287

GnomAD3 exomes

AF:

0.00239

AC:

579

AN:

242080

Hom.:

AF XY:

0.00246

AC XY:

326

AN XY:

132368

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00127

Gnomad ASJ exome

AF:

0.000102

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000958

Gnomad FIN exome

AF:

0.00217

Gnomad NFE exome

AF:

0.00397

Gnomad OTH exome

AF:

0.00221

GnomAD4 exome

AF:

0.00470

AC:

6848

AN:

1457638

Hom.:

Cov.:

AF XY:

0.00463

AC XY:

3356

AN XY:

724780

show subpopulations

Gnomad4 AFR exome

AF:

0.000838

Gnomad4 AMR exome

AF:

0.00124

Gnomad4 ASJ exome

AF:

0.0000385

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00111

Gnomad4 FIN exome

AF:

0.00153

Gnomad4 NFE exome

AF:

0.00569

Gnomad4 OTH exome

AF:

0.00439

GnomAD4 genome

AF:

0.00294

AC:

448

AN:

152288

Hom.:

Cov.:

AF XY:

0.00250

AC XY:

186

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00111

Gnomad4 AMR

AF:

0.00137

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000621

Gnomad4 FIN

AF:

0.00179

Gnomad4 NFE

AF:

0.00519

Gnomad4 OTH

AF:

0.00284

Alfa

AF:

0.00376

Hom.:

Bravo

AF:

0.00304

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00519

AC:

ESP6500AA

AF:

0.000242

AC:

ESP6500EA

AF:

0.00443

AC:

ExAC

AF:

0.00235

AC:

284

EpiCase

AF:

0.00360

EpiControl

AF:

0.00381

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

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: BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.090

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.49

MetaRNN

Benign

0.0054

MetaSVM

Benign

-0.93

MutationAssessor

Benign

0.34

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-0.32

REVEL

Benign

0.017

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Vest4

0.17

MVP

0.16

MPC

1.6

ClinPred

0.067

GERP RS

2.7

Varity_R

0.091

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over