rs2235544

Variant names:

• chr1-53909897-C-A
• rs2235544
• NM_000792.7:c.682-34C>A

Your query was ambiguous. Multiple possible variants found:

• chr1-53909897-C-A
• chr1-53909897-C-G
• chr1-53909897-C-T

Variant summary

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

The NM_000792.7(DIO1):​c.682-34C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.516 in 1,607,938 control chromosomes in the GnomAD database, including 220,048 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (no stars).

• Frequency:
  • Genomes: 𝑓 0.45 (16505 hom., cov: 32)
  • Exomes 𝑓: 0.52 (203543 hom.)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: drug response no assertion criteria provided O:1
• Conservation: PhyloP100: 0.0130
• Publications: 62 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.606 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.682-34C>A		intron	N/A	NP_000783.2
	DIO1	NM_001039715.3		c.538-34C>A		intron	N/A	NP_001034804.1	P49895-4
	DIO1	NM_213593.5		c.490-34C>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.682-34C>A		intron	N/A	ENSP00000354643.4	P49895-1
	DIO1	ENST00000388876.3	TSL:1	c.538-34C>A		intron	N/A	ENSP00000373528.3	P49895-4
	DIO1	ENST00000525202.5	TSL:1	c.490-34C>A		intron	N/A	ENSP00000435725.1	P49895-2

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67674 AN: 151844 Hom.: 16490 Cov.: 32

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.257

Gnomad AMR AF: 0.585

Gnomad ASJ AF: 0.407

Gnomad EAS AF: 0.472

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.551

Gnomad MID AF: 0.380

Gnomad NFE AF: 0.517

Gnomad OTH AF: 0.429

GnomAD2 exomes AF: 0.531 AC: 132485 AN: 249382 AF XY: 0.533

Gnomad AFR exome AF: 0.233

Gnomad AMR exome AF: 0.710

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.488

Gnomad FIN exome AF: 0.540

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.522

GnomAD4 exome AF: 0.523 AC: 761769 AN: 1455976 Hom.: 203543 Cov.: 29 AF XY: 0.526 AC XY: 381038 AN XY: 724736

African (AFR) AF: 0.216 AC: 7218 AN: 33362

American (AMR) AF: 0.691 AC: 30895 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10378 AN: 26104

East Asian (EAS) AF: 0.440 AC: 17447 AN: 39670

South Asian (SAS) AF: 0.629 AC: 54168 AN: 86152

European-Finnish (FIN) AF: 0.541 AC: 28897 AN: 53370

Middle Eastern (MID) AF: 0.378 AC: 2172 AN: 5748

European-Non Finnish (NFE) AF: 0.525 AC: 580931 AN: 1106684

Other (OTH) AF: 0.493 AC: 29663 AN: 60188

GnomAD4 genome AF: 0.446 AC: 67713 AN: 151962 Hom.: 16505 Cov.: 32 AF XY: 0.452 AC XY: 33550 AN XY: 74256

African (AFR) AF: 0.235 AC: 9747 AN: 41452

American (AMR) AF: 0.586 AC: 8947 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.407 AC: 1410 AN: 3466

East Asian (EAS) AF: 0.471 AC: 2434 AN: 5166

South Asian (SAS) AF: 0.625 AC: 3012 AN: 4822

European-Finnish (FIN) AF: 0.551 AC: 5798 AN: 10524

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.517 AC: 35102 AN: 67940

Other (OTH) AF: 0.433 AC: 912 AN: 2108

Alfa AF: 0.489 Hom.: 68673

Bravo AF: 0.435

Asia WGS AF: 0.535 AC: 1860 AN: 3478

ClinVar

ClinVar submissions

Significance: drug response

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Levothyroxine response (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	2.1
DANN	Benign	0.45
PhyloP100		0.013
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: rs2235544; hg19: chr1-54375570; COSMIC: COSV59519232; COSMIC: COSV59519232;