rs530719719

Variant names:

• chr15-45101227-TGAAC-T
• rs530719719
• NM_001363711.2:c.2895_2898delGTTC

Your query was ambiguous. Multiple possible variants found:

• chr15-45101227-TGAAC-T
• chr15-45101227-TGAAC-TGAACGAAC

Variant summary

Our verdict is Pathogenic. The variant received 19 ACMG points: 20P and 1B. PVS1 PS3 PP5_Very_Strong BS2_Supporting

The NM_001363711.2(DUOX2):​c.2895_2898delGTTC​(p.Phe966SerfsTer29) variant causes a frameshift change. The variant allele was found at a frequency of 0.00284 in 1,613,794 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000221187: Functional studies demonstrate that this variant results in complete inhibition of hydrogen peroxide-generating activity as well as decreased cell surface expression compared to wild-type (De Marco 2011 PMID:21565790)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. S965S) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (12 hom.)
• Consequence: DUOX2 NM_001363711.2 frameshift
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:24
• Conservation: PhyloP100: 4.91
• Publications: 18 publications found

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]

DUOX2 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 6

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 19 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000221187: Functional studies demonstrate that this variant results in complete inhibition of hydrogen peroxide-generating activity as well as decreased cell surface expression compared to wild-type (De Marco 2011 PMID:21565790).; SCV000321567: Published functional studies demonstrate complete inhibition of the hydrogen peroxide-generating activity as well as decreased cell surface expression (De Marco et al., 2011).; SCV000742851: Functional in vitro analyses performed on this mutation demonstrate nearly complete inhibition of hydrogen peroxide generation (De Marco, 2011; Muzza, 2014) and reduced cell surface protein expression compared to wildtype (De Marco, 2011).; SCV001142447: Functional studies confirmed that this mutation is responsible for the defect in H2O2 production (PMID: 21565790).; SCV001443718: This variant was shown to results in nonsense mediated mRNA decay (PMID: 24423310) and complete inhibition of the hydrogen peroxide-generating activity as well as decreased cell surface expression in in-vitro experiments based on expression of wild-type and mutant cDNA constructs in Hela cells (PMID: 24423310, 21565790).; SCV004047016: Experimental studies have shown that this frameshift variant results in nonsense mediated decay (Muzza M. et al. 2014).; SCV005395168: In functional assays, the variant resulted in reduced function (De Marco_2011). PMID:24423310
• PP5: Variant 15-45101227-TGAAC-T is Pathogenic according to our data. Variant chr15-45101227-TGAAC-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 189229.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001363711.2. 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
	DUOX2	NM_001363711.2	MANE Select	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	NP_001350640.1	X6RAN8
	DUOX2	NM_014080.5		c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	NP_054799.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX2	ENST00000389039.11	TSL:1 MANE Select	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	ENSP00000373691.7	X6RAN8
	DUOX2	ENST00000603300.1	TSL:1	c.2895_2898delGTTC	p.Phe966SerfsTer29	frameshift	Exon 22 of 34	ENSP00000475084.1	Q9NRD8
	DUOX2	ENST00000558383.1	TSL:5	n.5144_5147delGTTC		non_coding_transcript_exon	Exon 15 of 17

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152176 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.000845

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00294 AC: 736 AN: 250634 AF XY: 0.00288

Gnomad AFR exome AF: 0.000621

Gnomad AMR exome AF: 0.00162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00291

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00286 AC: 4183 AN: 1461500 Hom.: 12 AF XY: 0.00287 AC XY: 2087 AN XY: 726996

African (AFR) AF: 0.000299 AC: 10 AN: 33476

American (AMR) AF: 0.00179 AC: 80 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00265 AC: 228 AN: 86180

European-Finnish (FIN) AF: 0.0112 AC: 598 AN: 53290

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00279 AC: 3100 AN: 1111900

Other (OTH) AF: 0.00268 AC: 162 AN: 60386

GnomAD4 genome AF: 0.00261 AC: 398 AN: 152294 Hom.: 2 Cov.: 32 AF XY: 0.00279 AC XY: 208 AN XY: 74470

African (AFR) AF: 0.000842 AC: 35 AN: 41546

American (AMR) AF: 0.00203 AC: 31 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00228 AC: 11 AN: 4830

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000667 Hom.: 0

Bravo AF: 0.00207

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00360

EpiControl AF: 0.00273

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
12	-	-	Thyroid dyshormonogenesis 6 (12)
6	-	-	not provided (6)
1	-	-	Congenital hypothyroidism (1)
1	-	-	DUOX2-related disorder (1)
1	-	-	Familial thyroid dyshormonogenesis (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Nongoitrous Euthyroid Hyperthyrotropinemia (1)
1	-	-	Thyroid dyshormonogenesis 6;C4273748:Familial thyroid dyshormonogenesis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.9
Mutation Taster		=12/188	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.27		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.27		Position offset: -22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs530719719; hg19: chr15-45393425; COSMIC: COSV66531359; COSMIC: COSV66531359;