chr1-53904591-A-T

Variant names:

• chr1-53904591-A-T
• rs2294511
• NM_000792.7:c.338-75A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000792.7(DIO1):​c.338-75A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,547,958 control chromosomes in the GnomAD database, including 96,797 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 0.37 (10691 hom., cov: 31)
  • Exomes 𝑓: 0.35 (86106 hom.)
• Consequence: DIO1 NM_000792.7 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.743
• Publications: 8 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=-0.89).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.481 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	NM_000792.7	MANE Select	c.338-75A>T		intron	N/A	NP_000783.2
	DIO1	NM_001039715.3		c.338-1504A>T		intron	N/A	NP_001034804.1	P49895-4
	DIO1	NM_213593.5		c.146-75A>T		intron	N/A	NP_998758.1	P49895-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIO1	ENST00000361921.8	TSL:1 MANE Select	c.338-75A>T		intron	N/A	ENSP00000354643.4	P49895-1
	DIO1	ENST00000388876.3	TSL:1	c.338-1504A>T		intron	N/A	ENSP00000373528.3	P49895-4
	DIO1	ENST00000525202.5	TSL:1	c.146-75A>T		intron	N/A	ENSP00000435725.1	P49895-2

Frequencies

GnomAD3 genomes AF: 0.370 AC: 56186 AN: 151824 Hom.: 10678 Cov.: 31

Gnomad AFR AF: 0.402

Gnomad AMI AF: 0.490

Gnomad AMR AF: 0.490

Gnomad ASJ AF: 0.352

Gnomad EAS AF: 0.263

Gnomad SAS AF: 0.338

Gnomad FIN AF: 0.272

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.348

Gnomad OTH AF: 0.388

GnomAD4 exome AF: 0.348 AC: 486424 AN: 1396016 Hom.: 86106 AF XY: 0.347 AC XY: 241084 AN XY: 693844

African (AFR) AF: 0.409 AC: 12830 AN: 31360

American (AMR) AF: 0.517 AC: 20481 AN: 39636

Ashkenazi Jewish (ASJ) AF: 0.338 AC: 7933 AN: 23488

East Asian (EAS) AF: 0.269 AC: 10470 AN: 38914

South Asian (SAS) AF: 0.348 AC: 27260 AN: 78360

European-Finnish (FIN) AF: 0.292 AC: 15154 AN: 51862

Middle Eastern (MID) AF: 0.343 AC: 1848 AN: 5386

European-Non Finnish (NFE) AF: 0.346 AC: 369739 AN: 1069252

Other (OTH) AF: 0.359 AC: 20709 AN: 57758

GnomAD4 genome AF: 0.370 AC: 56230 AN: 151942 Hom.: 10691 Cov.: 31 AF XY: 0.368 AC XY: 27347 AN XY: 74280

African (AFR) AF: 0.402 AC: 16644 AN: 41392

American (AMR) AF: 0.491 AC: 7491 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.352 AC: 1221 AN: 3470

East Asian (EAS) AF: 0.263 AC: 1358 AN: 5156

South Asian (SAS) AF: 0.337 AC: 1622 AN: 4814

European-Finnish (FIN) AF: 0.272 AC: 2879 AN: 10566

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.348 AC: 23633 AN: 67962

Other (OTH) AF: 0.392 AC: 825 AN: 2106

Alfa AF: 0.366 Hom.: 1420

Bravo AF: 0.385

Asia WGS AF: 0.338 AC: 1175 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.26
DANN	Benign	0.48
PhyloP100		-0.74
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: rs2294511; hg19: chr1-54370264; COSMIC: COSV59517415;