15-45099368-A-T

Position:

• chr15-45099368-A-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.3515+15T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,612,502 control chromosomes in the GnomAD database, including 804,285 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.99 (75080 hom., cov: 31)
  • Exomes 𝑓: 1.0 (729205 hom.)
• Consequence: DUOX2 NM_001363711.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.749

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=-0.73).
• BP6: Variant 15-45099368-A-T is Benign according to our data. Variant chr15-45099368-A-T is described in ClinVar as [Benign]. Clinvar id is 260324.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45099368-A-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOX2	NM_001363711.2	c.3515+15T>A		intron_variant		ENST00000389039.11
DUOX2	NM_014080.5	c.3515+15T>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOX2	ENST00000389039.11	c.3515+15T>A		intron_variant		1	NM_001363711.2	P4
DUOX2	ENST00000603300.1	c.3515+15T>A		intron_variant		1		A1
DUOX2	ENST00000558383.1	n.6302T>A		non_coding_transcript_exon_variant	17/17	5

Frequencies

GnomAD3 genomes AF: 0.993 AC: 151075 AN: 152128 Hom.: 75025 Cov.: 31

Gnomad AFR AF: 0.976

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 1.00

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.993

GnomAD3 exomes AF: 0.998 AC: 250786 AN: 251232 Hom.: 125179 AF XY: 0.999 AC XY: 135616 AN XY: 135802

Gnomad AFR exome AF: 0.974

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad SAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1459318 AN: 1460256 Hom.: 729205 Cov.: 34 AF XY: 0.999 AC XY: 726198 AN XY: 726606

Gnomad4 AFR exome AF: 0.976

Gnomad4 AMR exome AF: 0.999

Gnomad4 ASJ exome AF: 1.00

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 1.00

Gnomad4 FIN exome AF: 1.00

Gnomad4 NFE exome AF: 1.00

Gnomad4 OTH exome AF: 0.999

GnomAD4 genome AF: 0.993 AC: 151189 AN: 152246 Hom.: 75080 Cov.: 31 AF XY: 0.993 AC XY: 73950 AN XY: 74438

Gnomad4 AFR AF: 0.976

Gnomad4 AMR AF: 0.999

Gnomad4 ASJ AF: 1.00

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 1.00

Gnomad4 FIN AF: 1.00

Gnomad4 NFE AF: 1.00

Gnomad4 OTH AF: 0.993

Alfa AF: 0.997 Hom.: 13885

Bravo AF: 0.992

Asia WGS AF: 0.998 AC: 3471 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Thyroid dyshormonogenesis 6 Benign:3

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. -
Benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	3.8
DANN	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs269869; hg19: chr15-45391566;