ENST00000510508.5:c.35G>A

Variant names:

• chr14-101561531-G-A
• rs199500701
• NM_001362.4:c.35G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000510508.5(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. 11/19 in silico tools predict 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 ENST00000510508.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.77
• Publications: 6 publications found

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

Our verdict: Benign. The variant received -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 VariationId is 3770501.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 448 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000510508.5. 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
	DIO3	NM_001362.4	MANE Select	c.35G>A	p.Gly12Glu	missense	Exon 1 of 1	NP_001353.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO3	ENST00000510508.5	TSL:6 MANE Select	c.35G>A	p.Gly12Glu	missense	Exon 1 of 1	ENSP00000427336.3	P55073
	DIO3	ENST00000700173.1		c.-312-173G>A		intron	N/A	ENSP00000514840.1	A0A8V8TPY2
	DIO3OS	ENST00000700197.1		n.1129-2697C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 448 AN: 152170 Hom.: 1 Cov.: 32

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

GnomAD2 exomes AF: 0.00239 AC: 579 AN: 242080 AF XY: 0.00246

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 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.: 29 Cov.: 31 AF XY: 0.00463 AC XY: 3356 AN XY: 724780

African (AFR) AF: 0.000838 AC: 28 AN: 33412

American (AMR) AF: 0.00124 AC: 55 AN: 44368

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25974

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39602

South Asian (SAS) AF: 0.00111 AC: 95 AN: 85972

European-Finnish (FIN) AF: 0.00153 AC: 80 AN: 52324

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.00569 AC: 6321 AN: 1110046

Other (OTH) AF: 0.00439 AC: 264 AN: 60180

GnomAD4 genome AF: 0.00294 AC: 448 AN: 152288 Hom.: 1 Cov.: 32 AF XY: 0.00250 AC XY: 186 AN XY: 74460

African (AFR) AF: 0.00111 AC: 46 AN: 41554

American (AMR) AF: 0.00137 AC: 21 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00179 AC: 19 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00519 AC: 353 AN: 68022

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00341 Hom.: 2

Bravo AF: 0.00304

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.000242 AC: 1

ESP6500EA AF: 0.00443 AC: 37

ExAC AF: 0.00235 AC: 284

EpiCase AF: 0.00360

EpiControl AF: 0.00381

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.090	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.29
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.49	T
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.017
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Vest4		0.17
MVP		0.16
MPC		1.6
ClinPred		0.067	T
GERP RS		2.7
PromoterAI		-0.028	Neutral
Varity_R		0.091
Mutation Taster		=97/3	polymorphism

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

dbSNP: rs199500701; hg19: chr14-102027868; COSMIC: COSV106109730; COSMIC: COSV106109730;