chr15-45093718-C-T

Position:

• chr15-45093718-C-T

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.*432G>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 0.186 in 193,802 control chromosomes in the GnomAD database, including 7,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.21 (7283 hom., cov: 32)
  • Exomes 𝑓: 0.091 (455 hom.)
• Consequence: DUOX2 NM_001363711.2 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.05

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=-0.9).
• BP6: Variant 15-45093718-C-T is Benign according to our data. Variant chr15-45093718-C-T is described in ClinVar as [Benign]. Clinvar id is 316130.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.564 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX2	NM_001363711.2	c.*432G>A		3_prime_UTR_variant	34/34	ENST00000389039.11	NP_001350640.1
DUOX2	NM_014080.5	c.*432G>A		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.*432G>A		3_prime_UTR_variant	34/34	1	NM_001363711.2	ENSP00000373691	P4
DUOX2	ENST00000603300.1	c.*432G>A		3_prime_UTR_variant	34/34	1		ENSP00000475084	A1

Frequencies

GnomAD3 genomes AF: 0.212 AC: 32209 AN: 151952 Hom.: 7256 Cov.: 32

Gnomad AFR AF: 0.570

Gnomad AMI AF: 0.0461

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0686

Gnomad EAS AF: 0.0495

Gnomad SAS AF: 0.0534

Gnomad FIN AF: 0.0756

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0710

Gnomad OTH AF: 0.155

GnomAD4 exome AF: 0.0909 AC: 3794 AN: 41732 Hom.: 455 Cov.: 0 AF XY: 0.0859 AC XY: 1888 AN XY: 21988

Gnomad4 AFR exome AF: 0.573

Gnomad4 AMR exome AF: 0.118

Gnomad4 ASJ exome AF: 0.0535

Gnomad4 EAS exome AF: 0.0452

Gnomad4 SAS exome AF: 0.0501

Gnomad4 FIN exome AF: 0.0489

Gnomad4 NFE exome AF: 0.0618

Gnomad4 OTH exome AF: 0.0910

GnomAD4 genome AF: 0.212 AC: 32293 AN: 152070 Hom.: 7283 Cov.: 32 AF XY: 0.206 AC XY: 15344 AN XY: 74348

Gnomad4 AFR AF: 0.570

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0686

Gnomad4 EAS AF: 0.0494

Gnomad4 SAS AF: 0.0536

Gnomad4 FIN AF: 0.0756

Gnomad4 NFE AF: 0.0710

Gnomad4 OTH AF: 0.158

Alfa AF: 0.0901 Hom.: 1516

Bravo AF: 0.232

Asia WGS AF: 0.124 AC: 431 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	-0.90
CADD	Benign	0.15
DANN	Benign	0.51

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: rs10851420; hg19: chr15-45385916;