1-53906216-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000792.7(DIO1):c.603G>A(p.Met201Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000945 in 1,614,226 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00099 (22 hom.)
• Consequence: DIO1 NM_000792.7 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.19

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

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009709507).
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.000985 (1440/1461866) while in subpopulation SAS AF= 0.0158 (1362/86258). AF 95% confidence interval is 0.0151. There are 22 homozygotes in gnomad4_exome. There are 1042 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 87 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DIO1	NM_000792.7	c.603G>A	p.Met201Ile	missense_variant	3/4	ENST00000361921.8
LOC124904180	XR_007066095.1	n.288+195C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DIO1	ENST00000361921.8	c.603G>A	p.Met201Ile	missense_variant	3/4	1	NM_000792.7	P1

Frequencies

GnomAD3 genomes AF: 0.000571 AC: 87 AN: 152242 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0174

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00196 AC: 493 AN: 251072 Hom.: 7 AF XY: 0.00270 AC XY: 367 AN XY: 135724

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0157

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.000980

GnomAD4 exome AF: 0.000985 AC: 1440 AN: 1461866 Hom.: 22 Cov.: 31 AF XY: 0.00143 AC XY: 1042 AN XY: 727234

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0158

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000153

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.000564 AC: 86 AN: 152360 Hom.: 0 Cov.: 32 AF XY: 0.000832 AC XY: 62 AN XY: 74518

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0172

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.000128

ExAC AF: 0.00222 AC: 270

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Thyroid hormone metabolism, abnormal, 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 26, 2022

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.084	T
BayesDel_noAF	Uncertain	0.12
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.0097	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.48	T
PROVEAN	Uncertain	-3.7	D;D;.;D;D;D
REVEL	Uncertain	0.44
Sift	Uncertain	0.0020	D;D;.;D;D;D
Sift4G	Benign	0.19	T;T;T;T;T;T
Polyphen		0.98, 1.0, 1.0	.;D;.;D;.;D
Vest4		0.80, 0.79, 0.79
MutPred		0.86		.;Loss of catalytic residue at V197 (P = 0.0412);.;.;.;.;
MVP		0.75
MPC		0.62
ClinPred		0.10	T
GERP RS		4.9
Varity_R		0.84

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

LitVar

Other links and lift over

dbSNP: rs201420507; hg19: chr1-54371889; COSMIC: COSV59518628; COSMIC: COSV59518628;