chr1-53904633-G-A

Variant names:

• chr1-53904633-G-A
• rs2294512
• NM_000792.7:c.338-33G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000792.7(DIO1):​c.338-33G>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
• Publications: 18 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=-0.95).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.605 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.338-33G>A		intron	N/A	NP_000783.2
	DIO1	NM_001039715.3		c.338-1462G>A		intron	N/A	NP_001034804.1	P49895-4
	DIO1	NM_213593.5		c.146-33G>A		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.338-33G>A		intron	N/A	ENSP00000354643.4	P49895-1
	DIO1	ENST00000388876.3	TSL:1	c.338-1462G>A		intron	N/A	ENSP00000373528.3	P49895-4
	DIO1	ENST00000525202.5	TSL:1	c.146-33G>A		intron	N/A	ENSP00000435725.1	P49895-2

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

GnomAD2 exomes AF: 0.331 AC: 79792 AN: 241202 AF XY: 0.325

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 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

African (AFR) AF: 0.499 AC: 16364 AN: 32786

American (AMR) AF: 0.288 AC: 12244 AN: 42498

Ashkenazi Jewish (ASJ) AF: 0.232 AC: 5940 AN: 25636

East Asian (EAS) AF: 0.629 AC: 24881 AN: 39538

South Asian (SAS) AF: 0.339 AC: 28738 AN: 84652

European-Finnish (FIN) AF: 0.306 AC: 16293 AN: 53220

Middle Eastern (MID) AF: 0.222 AC: 1268 AN: 5702

European-Non Finnish (NFE) AF: 0.290 AC: 320567 AN: 1105998

Other (OTH) AF: 0.310 AC: 18518 AN: 59806

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

African (AFR) AF: 0.485 AC: 20068 AN: 41368

American (AMR) AF: 0.263 AC: 4016 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.234 AC: 811 AN: 3464

East Asian (EAS) AF: 0.623 AC: 3210 AN: 5154

South Asian (SAS) AF: 0.356 AC: 1711 AN: 4810

European-Finnish (FIN) AF: 0.311 AC: 3279 AN: 10548

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.284 AC: 19316 AN: 67960

Other (OTH) AF: 0.297 AC: 625 AN: 2106

Alfa AF: 0.312 Hom.: 17656

Bravo AF: 0.356

Asia WGS AF: 0.499 AC: 1735 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.70
DANN	Benign	0.24
PhyloP100		-0.061
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: rs2294512; hg19: chr1-54370306;