chr15-45117274-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_207581.4(DUOXA2):c.738C>T(p.Tyr246Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,603,938 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 28 hom., cov: 33)

Exomes 𝑓: 0.011 ( 195 hom. )

Consequence

DUOXA2
NM_207581.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -1.77

Publications

40 publications found

Variant links:

Genes affected

DUOXA2 (HGNC:32698): (dual oxidase maturation factor 2) This gene encodes an endoplasmic reticulum protein that is necessary for proper cellular localization and maturation of functional dual oxidase 2. Mutations in this gene have been associated with thyroid dyshormonogenesis 5.[provided by RefSeq, Feb 2010]

DUOXA2 links:

DUOXA1 (HGNC:26507): (dual oxidase maturation factor 1) Dual oxidases DUOX1 and DUOX2 are NADPH oxidases which are involved in hydrogen peroxide production necessary for thyroid hormonogenesis. They form a heterodimer with specific maturation factors DUOXA1 and DUOXA2, respectively, which is essential for the maturation and function of the DUOX enzyme complexes. This gene encodes the DUOX1 activator or maturation factor DUOXA1. Rat studies identified a bidirectional promoter which controls the transcription of the DUOX1 and DUOXA1 genes. This protein is cotransported to the cell surface when coexpressed with DUOX1 and is retained in the endoplasmic reticulum when expressed without DUOX1 protein. The expression of this gene or the DUOX1 gene is not suppressed by thyroglobulin (Tg), a macromolecular precursor in thyroid hormone synthesis, while the expression of the DUOX2 and DUOXA2 are significantly suppressed by the Tg. This protein is also a p53-regulated neurogenic factor involved in p53 dependent neuronal differentiation. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

DUOXA1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 15-45117274-C-T is Benign according to our data. Variant chr15-45117274-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.77 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOXA2	NM_207581.4 link	c.738C>T	p.Tyr246Tyr	synonymous_variant	Exon 5 of 6	ENST00000323030.6	NP_997464.2	Q1HG44-1
DUOXA1	NM_001276266.2 link	c.*1832G>A		downstream_gene_variant		ENST00000560572.6	NP_001263195.1	Q1HG43-1B5M0B7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOXA2	ENST00000323030.6 link	c.738C>T	p.Tyr246Tyr	synonymous_variant	Exon 5 of 6	1	NM_207581.4	ENSP00000319705.5		Q1HG44-1
DUOXA1	ENST00000560572.6 link	c.*1832G>A		downstream_gene_variant		1	NM_001276266.2	ENSP00000454084.1		Q1HG43-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1936

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0106

Gnomad AMI

AF:

0.0582

Gnomad AMR

AF:

0.0204

Gnomad ASJ

AF:

0.00461

Gnomad EAS

AF:

0.0565

Gnomad SAS

AF:

0.00807

Gnomad FIN

AF:

0.0121

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00916

Gnomad OTH

AF:

0.0138

GnomAD2 exomes

AF:

0.0169

AC:

4019

AN:

237622

AF XY:

0.0154

show subpopulations

Gnomad AFR exome

AF:

0.0102

Gnomad AMR exome

AF:

0.0378

Gnomad ASJ exome

AF:

0.00280

Gnomad EAS exome

AF:

0.0539

Gnomad FIN exome

AF:

0.00883

Gnomad NFE exome

AF:

0.0104

Gnomad OTH exome

AF:

0.0141

GnomAD4 exome

AF:

0.0111

AC:

16121

AN:

1451584

Hom.:

195

Cov.:

AF XY:

0.0108

AC XY:

7797

AN XY:

720750

show subpopulations

African (AFR)

AF:

0.0107

AC:

357

AN:

33330

American (AMR)

AF:

0.0345

AC:

1529

AN:

44258

Ashkenazi Jewish (ASJ)

AF:

0.00278

AC:

AN:

25856

East Asian (EAS)

AF:

0.0617

AC:

2436

AN:

39474

South Asian (SAS)

AF:

0.00759

AC:

649

AN:

85482

European-Finnish (FIN)

AF:

0.00971

AC:

496

AN:

51102

Middle Eastern (MID)

AF:

0.00387

AC:

AN:

5678

European-Non Finnish (NFE)

AF:

0.00889

AC:

9837

AN:

1106502

Other (OTH)

AF:

0.0121

AC:

723

AN:

59902

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.491

Heterozygous variant carriers

971

1942

2913

3884

4855

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

418

836

1254

1672

2090

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0128

AC:

1945

AN:

152354

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

978

AN XY:

74494

show subpopulations

African (AFR)

AF:

0.0107

AC:

445

AN:

41594

American (AMR)

AF:

0.0204

AC:

313

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00461

AC:

AN:

3470

East Asian (EAS)

AF:

0.0561

AC:

290

AN:

5170

South Asian (SAS)

AF:

0.00870

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0121

AC:

129

AN:

10626

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00916

AC:

623

AN:

68036

Other (OTH)

AF:

0.0151

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

193

289

386

482

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00942

Hom.:

Bravo

AF:

0.0139

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Jul 09, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

0.34

(source)

DANN

Benign

0.85

PhyloP100

-1.8

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over