1-53902580-A-C

Variant names:

• chr1-53902580-A-C
• rs731828
• NM_000792.7:c.338-2086A>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 13 publications found

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

Our verdict: Benign. The variant received -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000792.7. 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
	DIO1	NM_000792.7	MANE Select	c.338-2086A>C		intron	N/A	NP_000783.2
	DIO1	NM_001039715.3		c.338-3515A>C		intron	N/A	NP_001034804.1	P49895-4
	DIO1	NM_213593.5		c.146-2086A>C		intron	N/A	NP_998758.1	P49895-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	ENST00000361921.8	TSL:1 MANE Select	c.338-2086A>C		intron	N/A	ENSP00000354643.4	P49895-1
	DIO1	ENST00000388876.3	TSL:1	c.338-3515A>C		intron	N/A	ENSP00000373528.3	P49895-4
	DIO1	ENST00000525202.5	TSL:1	c.146-2086A>C		intron	N/A	ENSP00000435725.1	P49895-2

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

African (AFR) AF: 0.452 AC: 18578 AN: 41066

American (AMR) AF: 0.298 AC: 4543 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 938 AN: 3466

East Asian (EAS) AF: 0.558 AC: 2875 AN: 5154

South Asian (SAS) AF: 0.417 AC: 2012 AN: 4822

European-Finnish (FIN) AF: 0.474 AC: 5001 AN: 10550

Middle Eastern (MID) AF: 0.284 AC: 83 AN: 292

European-Non Finnish (NFE) AF: 0.382 AC: 25986 AN: 67948

Other (OTH) AF: 0.372 AC: 781 AN: 2100

Alfa AF: 0.379 Hom.: 14222

Bravo AF: 0.394

Asia WGS AF: 0.452 AC: 1571 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	6.7
DANN	Benign	0.56
PhyloP100		0.64
Mutation Taster		=100/0	polymorphism (auto)

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