rs2294512

Positions:

• chr1-53904633-G-A
• chr1-53904633-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000792.7(DIO1):​c.338-33G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.311 in 1,601,710 control chromosomes in the GnomAD database, including 82,266 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (10158 hom., cov: 31)
  • Exomes 𝑓: 0.31 (72108 hom.)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0610

Genes affected

DIO1 (HGNC:2883): (iodothyronine deiodinase 1) The protein encoded by this gene belongs to the iodothyronine deiodinase family. It catalyzes the activation, as well as the inactivation of thyroid hormone by outer and inner ring deiodination, respectively. The activation reaction involves the conversion of the prohormone thyroxine (3,5,3',5'-tetraiodothyronine, T4), secreted by the thyroid gland, to the bioactive thyroid hormone (3,5,3'-triiodothyronine, T3) by 5'-deiodination. This protein provides most of the circulating T3, which is essential for growth, differentiation and basal metabolism in vertebrates. This protein is a selenoprotein, containing the rare amino acid selenocysteine (Sec) 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. Alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jun 2018]

LOC124904180 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIO1	NM_000792.7	c.338-33G>A		intron_variant		ENST00000361921.8
LOC124904180	XR_007066095.1	n.288+1778C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIO1	ENST00000361921.8	c.338-33G>A		intron_variant		1	NM_000792.7	P1

Frequencies

GnomAD3 genomes AF: 0.351 AC: 53209 AN: 151756 Hom.: 10135 Cov.: 31

Gnomad AFR AF: 0.485

Gnomad AMI AF: 0.212

Gnomad AMR AF: 0.263

Gnomad ASJ AF: 0.234

Gnomad EAS AF: 0.623

Gnomad SAS AF: 0.357

Gnomad FIN AF: 0.311

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.284

Gnomad OTH AF: 0.297

GnomAD3 exomes AF: 0.331 AC: 79792 AN: 241202 Hom.: 14593 AF XY: 0.325 AC XY: 42577 AN XY: 131030

Gnomad AFR exome AF: 0.495

Gnomad AMR exome AF: 0.291

Gnomad ASJ exome AF: 0.230

Gnomad EAS exome AF: 0.633

Gnomad SAS exome AF: 0.337

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.286

Gnomad OTH exome AF: 0.287

GnomAD4 exome AF: 0.307 AC: 444813 AN: 1449836 Hom.: 72108 Cov.: 32 AF XY: 0.306 AC XY: 220836 AN XY: 721186

Gnomad4 AFR exome AF: 0.499

Gnomad4 AMR exome AF: 0.288

Gnomad4 ASJ exome AF: 0.232

Gnomad4 EAS exome AF: 0.629

Gnomad4 SAS exome AF: 0.339

Gnomad4 FIN exome AF: 0.306

Gnomad4 NFE exome AF: 0.290

Gnomad4 OTH exome AF: 0.310

GnomAD4 genome AF: 0.351 AC: 53280 AN: 151874 Hom.: 10158 Cov.: 31 AF XY: 0.350 AC XY: 25978 AN XY: 74212

Gnomad4 AFR AF: 0.485

Gnomad4 AMR AF: 0.263

Gnomad4 ASJ AF: 0.234

Gnomad4 EAS AF: 0.623

Gnomad4 SAS AF: 0.356

Gnomad4 FIN AF: 0.311

Gnomad4 NFE AF: 0.284

Gnomad4 OTH AF: 0.297

Alfa AF: 0.300 Hom.: 5161

Bravo AF: 0.356

Asia WGS AF: 0.499 AC: 1735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.70
DANN	Benign	0.24

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: rs2294512; hg19: chr1-54370306;