rs2294511

Positions:

• chr1-53904591-A-T

Variant summary

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

The NM_000792.7(DIO1):​c.338-75A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,547,958 control chromosomes in the GnomAD database, including 96,797 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 0.37 (10691 hom., cov: 31)
  • Exomes 𝑓: 0.35 (86106 hom.)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743

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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.481 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO1	NM_000792.7	c.338-75A>T		intron_variant		ENST00000361921.8	NP_000783.2
LOC124904180	XR_007066095.1	n.288+1820T>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO1	ENST00000361921.8	c.338-75A>T		intron_variant		1	NM_000792.7	ENSP00000354643	P1

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56186 AN: 151824 Hom.: 10678 Cov.: 31

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.348 AC: 486424 AN: 1396016 Hom.: 86106 AF XY: 0.347 AC XY: 241084 AN XY: 693844

Gnomad4 AFR exome AF: 0.409

Gnomad4 AMR exome AF: 0.517

Gnomad4 ASJ exome AF: 0.338

Gnomad4 EAS exome AF: 0.269

Gnomad4 SAS exome AF: 0.348

Gnomad4 FIN exome AF: 0.292

Gnomad4 NFE exome AF: 0.346

Gnomad4 OTH exome AF: 0.359

GnomAD4 genome AF: 0.370 AC: 56230 AN: 151942 Hom.: 10691 Cov.: 31 AF XY: 0.368 AC XY: 27347 AN XY: 74280

Gnomad4 AFR AF: 0.402

Gnomad4 AMR AF: 0.491

Gnomad4 ASJ AF: 0.352

Gnomad4 EAS AF: 0.263

Gnomad4 SAS AF: 0.337

Gnomad4 FIN AF: 0.272

Gnomad4 NFE AF: 0.348

Gnomad4 OTH AF: 0.392

Alfa AF: 0.366 Hom.: 1420

Bravo AF: 0.385

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.26
DANN	Benign	0.48

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: rs2294511; hg19: chr1-54370264; COSMIC: COSV59517415;