rs147857941

Variant names:

• chr1-53894357-T-A
• rs147857941
• NM_000792.7:c.147T>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BS2_Supporting

The NM_213593.5(DIO1):​c.145+2T>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000805 in 1,614,154 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: DIO1 NM_213593.5 splice_donor, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.31
• Publications: 0 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.664419).
• BP6: Variant 1-53894357-T-A is Benign according to our data. Variant chr1-53894357-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3501999.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_213593.5. 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.147T>A	p.Gly49Gly	synonymous	Exon 1 of 4	NP_000783.2
	DIO1	NM_001039715.3		c.147T>A	p.Gly49Gly	synonymous	Exon 1 of 3	NP_001034804.1	P49895-4
	DIO1	NM_001039716.3		c.147T>A	p.Gly49Gly	synonymous	Exon 1 of 3	NP_001034805.1	P49895-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	ENST00000361921.8	TSL:1 MANE Select	c.147T>A	p.Gly49Gly	synonymous	Exon 1 of 4	ENSP00000354643.4	P49895-1
	DIO1	ENST00000388876.3	TSL:1	c.147T>A	p.Gly49Gly	synonymous	Exon 1 of 3	ENSP00000373528.3	P49895-4
	DIO1	ENST00000322679.10	TSL:1	c.147T>A	p.Gly49Gly	synonymous	Exon 1 of 3	ENSP00000323198.6	P49895-5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 250782 AF XY: 0.0000147

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461894 Hom.: 0 Cov.: 31 AF XY: 0.00000550 AC XY: 4 AN XY: 727248

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152260 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74438

African (AFR) AF: 0.000144 AC: 6 AN: 41550

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2106

Alfa AF: 0.0000377 Hom.: 0

Bravo AF: 0.0000756

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.5
DANN	Benign	0.52
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.063	N
PhyloP100		-1.3
GERP RS		-8.1
PromoterAI		-0.014	Neutral
Mutation Taster		=89/11	polymorphism

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: rs147857941; hg19: chr1-54360030;