chr15-45093697-A-G

Position:

• chr15-45093697-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001363711.2(DUOX2):​c.*453T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0961 in 180,724 control chromosomes in the GnomAD database, including 1,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.10 (1077 hom., cov: 32)
  • Exomes 𝑓: 0.063 (67 hom.)
• Consequence: DUOX2 NM_001363711.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.00300

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 15-45093697-A-G is Benign according to our data. Variant chr15-45093697-A-G is described in ClinVar as [Benign]. Clinvar id is 316129.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.193 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.*453T>C		3_prime_UTR_variant	34/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.*453T>C		3_prime_UTR_variant	34/34		NP_054799.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX2	ENST00000389039.11	c.*453T>C		3_prime_UTR_variant	34/34	1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1	c.*453T>C		3_prime_UTR_variant	34/34	1		ENSP00000475084	A1

Frequencies

GnomAD3 genomes AF: 0.102 AC: 15560 AN: 152052 Hom.: 1078 Cov.: 32

Gnomad AFR AF: 0.196

Gnomad AMI AF: 0.0462

Gnomad AMR AF: 0.0751

Gnomad ASJ AF: 0.0687

Gnomad EAS AF: 0.0322

Gnomad SAS AF: 0.0503

Gnomad FIN AF: 0.0694

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0689

Gnomad OTH AF: 0.0748

GnomAD4 exome AF: 0.0625 AC: 1786 AN: 28554 Hom.: 67 Cov.: 0 AF XY: 0.0617 AC XY: 935 AN XY: 15164

Gnomad4 AFR exome AF: 0.194

Gnomad4 AMR exome AF: 0.0768

Gnomad4 ASJ exome AF: 0.0439

Gnomad4 EAS exome AF: 0.0278

Gnomad4 SAS exome AF: 0.0406

Gnomad4 FIN exome AF: 0.0458

Gnomad4 NFE exome AF: 0.0583

Gnomad4 OTH exome AF: 0.0635

GnomAD4 genome AF: 0.102 AC: 15588 AN: 152170 Hom.: 1077 Cov.: 32 AF XY: 0.100 AC XY: 7451 AN XY: 74424

Gnomad4 AFR AF: 0.196

Gnomad4 AMR AF: 0.0754

Gnomad4 ASJ AF: 0.0687

Gnomad4 EAS AF: 0.0325

Gnomad4 SAS AF: 0.0502

Gnomad4 FIN AF: 0.0694

Gnomad4 NFE AF: 0.0689

Gnomad4 OTH AF: 0.0773

Alfa AF: 0.0734 Hom.: 530

Bravo AF: 0.106

Asia WGS AF: 0.0640 AC: 221 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Thyroid dyshormonogenesis 6 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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	-0.84
CADD	Benign	2.7
DANN	Benign	0.55

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: rs3743222; hg19: chr15-45385895;