rs4926616

Variant names:

• chr1-53904057-T-C
• rs4926616
• NM_000792.7:c.338-609T>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.338-609T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 150,418 control chromosomes in the GnomAD database, including 31,653 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 0.65 (31653 hom., cov: 30)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0800
• Publications: 3 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.801 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	NM_000792.7	MANE Select	c.338-609T>C		intron	N/A	NP_000783.2
	DIO1	NM_001039715.3		c.338-2038T>C		intron	N/A	NP_001034804.1
	DIO1	NM_213593.5		c.146-609T>C		intron	N/A	NP_998758.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	ENST00000361921.8	TSL:1 MANE Select	c.338-609T>C		intron	N/A	ENSP00000354643.4
	DIO1	ENST00000388876.3	TSL:1	c.338-2038T>C		intron	N/A	ENSP00000373528.3
	DIO1	ENST00000525202.5	TSL:1	c.146-609T>C		intron	N/A	ENSP00000435725.1

Frequencies

GnomAD3 genomes AF: 0.646 AC: 97085 AN: 150300 Hom.: 31637 Cov.: 30

Gnomad AFR AF: 0.600

Gnomad AMI AF: 0.583

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.622

Gnomad EAS AF: 0.822

Gnomad SAS AF: 0.714

Gnomad FIN AF: 0.713

Gnomad MID AF: 0.615

Gnomad NFE AF: 0.663

Gnomad OTH AF: 0.626

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

GnomAD4 genome AF: 0.646 AC: 97151 AN: 150418 Hom.: 31653 Cov.: 30 AF XY: 0.648 AC XY: 47700 AN XY: 73556

African (AFR) AF: 0.600 AC: 24003 AN: 40004

American (AMR) AF: 0.575 AC: 8727 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.622 AC: 2158 AN: 3472

East Asian (EAS) AF: 0.821 AC: 4237 AN: 5158

South Asian (SAS) AF: 0.714 AC: 3433 AN: 4806

European-Finnish (FIN) AF: 0.713 AC: 7523 AN: 10552

Middle Eastern (MID) AF: 0.610 AC: 178 AN: 292

European-Non Finnish (NFE) AF: 0.663 AC: 45053 AN: 67936

Other (OTH) AF: 0.624 AC: 1307 AN: 2096

Alfa AF: 0.656 Hom.: 45633

Bravo AF: 0.629

Asia WGS AF: 0.737 AC: 2563 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.7
DANN	Benign	0.70
PhyloP100		-0.080
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: rs4926616; hg19: chr1-54369730;