rs2268181

Variant names:

• chr1-53895615-T-C
• rs2268181
• NM_000792.7:c.337+1068T>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.337+1068T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.15 in 152,112 control chromosomes in the GnomAD database, including 1,815 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 0.15 (1815 hom., cov: 32)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.609
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.239 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DIO1	NM_000792.7	c.337+1068T>C		intron_variant	Intron 1 of 3	ENST00000361921.8	NP_000783.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DIO1	ENST00000361921.8	c.337+1068T>C		intron_variant	Intron 1 of 3	1	NM_000792.7	ENSP00000354643.4

Frequencies

GnomAD3 genomes AF: 0.150 AC: 22799 AN: 151994 Hom.: 1815 Cov.: 32

Gnomad AFR AF: 0.101

Gnomad AMI AF: 0.114

Gnomad AMR AF: 0.188

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.158

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

GnomAD4 genome AF: 0.150 AC: 22786 AN: 152112 Hom.: 1815 Cov.: 32 AF XY: 0.150 AC XY: 11161 AN XY: 74360

African (AFR) AF: 0.100 AC: 4167 AN: 41492

American (AMR) AF: 0.188 AC: 2864 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.193 AC: 668 AN: 3470

East Asian (EAS) AF: 0.169 AC: 873 AN: 5168

South Asian (SAS) AF: 0.250 AC: 1205 AN: 4814

European-Finnish (FIN) AF: 0.112 AC: 1182 AN: 10592

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.167 AC: 11328 AN: 67988

Other (OTH) AF: 0.156 AC: 328 AN: 2108

Alfa AF: 0.163 Hom.: 5662

Bravo AF: 0.150

Asia WGS AF: 0.223 AC: 777 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	6.7
DANN	Benign	0.48
PhyloP100		0.61
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: rs2268181; hg19: chr1-54361288;