15-45093428-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001363711.2(DUOX2):c.*722G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.107 in 152,534 control chromosomes in the GnomAD database, including 1,156 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.11 (1156 hom., cov: 32)
  • Exomes 𝑓: 0.050 (0 hom.)
• Consequence: DUOX2 NM_001363711.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.21

Genes affected

DUOX2 (HGNC:13273): (dual oxidase 2) The protein encoded by this gene is a glycoprotein and a member of the NADPH oxidase family. The synthesis of thyroid hormone is catalyzed by a protein complex located at the apical membrane of thyroid follicular cells. This complex contains an iodide transporter, thyroperoxidase, and a peroxide generating system that includes this encoded protein and DUOX1. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 15-45093428-C-T is Benign according to our data. Variant chr15-45093428-C-T is described in ClinVar as [Benign]. Clinvar id is 316126.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.*722G>A		3_prime_UTR_variant	34/34	ENST00000389039.11
DUOX2	NM_014080.5	c.*722G>A		3_prime_UTR_variant	34/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.*722G>A		3_prime_UTR_variant	34/34	1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.*722G>A		3_prime_UTR_variant	34/34	1		A1

Frequencies

GnomAD3 genomes AF: 0.107 AC: 16196 AN: 151994 Hom.: 1155 Cov.: 32

Gnomad AFR AF: 0.201

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.0885

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.0487

Gnomad SAS AF: 0.0525

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0699

Gnomad OTH AF: 0.0813

GnomAD4 exome AF: 0.0498 AC: 21 AN: 422 Hom.: 0 Cov.: 0 AF XY: 0.0533 AC XY: 13 AN XY: 244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0417

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0476

Gnomad4 OTH exome AF: 0.200

GnomAD4 genome AF: 0.107 AC: 16232 AN: 152112 Hom.: 1156 Cov.: 32 AF XY: 0.105 AC XY: 7783 AN XY: 74368

Gnomad4 AFR AF: 0.201

Gnomad4 AMR AF: 0.0888

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.0486

Gnomad4 SAS AF: 0.0530

Gnomad4 FIN AF: 0.0760

Gnomad4 NFE AF: 0.0700

Gnomad4 OTH AF: 0.0851

Alfa AF: 0.0668 Hom.: 435

Bravo AF: 0.111

Asia WGS AF: 0.102 AC: 353 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Thyroid dyshormonogenesis 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
Cadd	Benign	0.15
Dann	Benign	0.38

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: rs8024922; hg19: chr15-45385626;