rs731828

Positions:

• chr1-53902580-A-C
• chr1-53902580-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.338-2086A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.404 in 151,572 control chromosomes in the GnomAD database, including 12,901 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 0.40 (12901 hom., cov: 31)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.639

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO1	NM_000792.7	c.338-2086A>C		intron_variant		ENST00000361921.8	NP_000783.2
LOC124904180	XR_007066095.1	n.288+3831T>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO1	ENST00000361921.8	c.338-2086A>C		intron_variant		1	NM_000792.7	ENSP00000354643	P1

Frequencies

GnomAD3 genomes AF: 0.404 AC: 61128 AN: 151456 Hom.: 12890 Cov.: 31

Gnomad AFR AF: 0.453

Gnomad AMI AF: 0.418

Gnomad AMR AF: 0.297

Gnomad ASJ AF: 0.271

Gnomad EAS AF: 0.558

Gnomad SAS AF: 0.416

Gnomad FIN AF: 0.474

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.372

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.404 AC: 61176 AN: 151572 Hom.: 12901 Cov.: 31 AF XY: 0.406 AC XY: 30120 AN XY: 74120

Gnomad4 AFR AF: 0.452

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.271

Gnomad4 EAS AF: 0.558

Gnomad4 SAS AF: 0.417

Gnomad4 FIN AF: 0.474

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.372

Alfa AF: 0.378 Hom.: 11343

Bravo AF: 0.394

Asia WGS AF: 0.452 AC: 1571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.7
DANN	Benign	0.56

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: rs731828; hg19: chr1-54368253; COSMIC: COSV59517608;