1-53894343-G-T

Position:

• chr1-53894343-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000792.7(DIO1):​c.133G>T​(p.Gly45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DIO1 NM_000792.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.02

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]

DIO1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIO1	NM_000792.7	c.133G>T	p.Gly45Cys	missense_variant	1/4	ENST00000361921.8	NP_000783.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIO1	ENST00000361921.8	c.133G>T	p.Gly45Cys	missense_variant	1/4	1	NM_000792.7	ENSP00000354643.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 15, 2023

The c.133G>T (p.G45C) alteration is located in exon 1 (coding exon 1) of the DIO1 gene. This alteration results from a G to T substitution at nucleotide position 133, causing the glycine (G) at amino acid position 45 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	.;T;.;T;.;.;.;.;.
Eigen	Benign	0.055
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	.;D;D;D;D;D;D;D;D
M_CAP	Benign	0.018	T
MetaRNN	Uncertain	0.46	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Uncertain	2.5	.;M;M;.;.;.;M;M;M
PrimateAI	Benign	0.31	T
PROVEAN	Uncertain	-3.4	D;D;D;.;.;.;D;N;D
REVEL	Benign	0.21
Sift	Uncertain	0.0010	D;D;D;.;.;.;D;D;D
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D
Polyphen		0.99, 0.99, 0.98, 1.0	.;D;D;.;.;.;.;D;D
Vest4		0.25, 0.32, 0.34, 0.34, 0.35, 0.44, 0.35, 0.36
MutPred		0.52		.;Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);Loss of disorder (P = 0.0037);
MVP		0.54
MPC		0.68
ClinPred		0.92	D
GERP RS		1.5
Varity_R		0.53

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-54360016;