chr15-45117534-C-G

Position:

chr15-45117534-C-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The ENST00000267803.8(DUOXA1):c.1433G>C(p.Arg478Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0917 in 1,560,270 control chromosomes in the GnomAD database, including 11,530 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.18 ( 4209 hom., cov: 32)

Exomes 𝑓: 0.083 ( 7321 hom. )

Consequence

DUOXA1
ENST00000267803.8 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.90

Variant links:

Genes affected

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:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.3753772E-4).

BP6

Variant 15-45117534-C-G is Benign according to our data. Variant chr15-45117534-C-G is described in ClinVar as [Benign]. Clinvar id is 1230800.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.419 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DUOXA1	NM_001276266.2 linkuse as main transcript	c.*1572G>C		3_prime_UTR_variant	9/9	ENST00000560572.6
DUOXA2	NM_207581.4 linkuse as main transcript	c.770-182C>G		intron_variant		ENST00000323030.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DUOXA1	ENST00000560572.6 linkuse as main transcript	c.*1572G>C		3_prime_UTR_variant	9/9	1	NM_001276266.2	P1	Q1HG43-1
DUOXA2	ENST00000323030.6 linkuse as main transcript	c.770-182C>G		intron_variant		1	NM_207581.4	P1	Q1HG44-1

Frequencies

GnomAD3 genomes

AF:

0.175

AC:

26653

AN:

151882

Hom.:

4183

Cov.:

show subpopulations

Gnomad AFR

AF:

0.423

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.126

Gnomad ASJ

AF:

0.0862

Gnomad EAS

AF:

0.0611

Gnomad SAS

AF:

0.0613

Gnomad FIN

AF:

0.0836

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.0734

Gnomad OTH

AF:

0.160

GnomAD3 exomes

AF:

0.103

AC:

17234

AN:

167146

Hom.:

1592

AF XY:

0.0971

AC XY:

8644

AN XY:

88980

show subpopulations

Gnomad AFR exome

AF:

0.433

Gnomad AMR exome

AF:

0.127

Gnomad ASJ exome

AF:

0.0847

Gnomad EAS exome

AF:

0.0559

Gnomad SAS exome

AF:

0.0723

Gnomad FIN exome

AF:

0.0739

Gnomad NFE exome

AF:

0.0742

Gnomad OTH exome

AF:

0.0922

GnomAD4 exome

AF:

0.0826

AC:

116335

AN:

1408270

Hom.:

7321

Cov.:

AF XY:

0.0812

AC XY:

56544

AN XY:

695946

show subpopulations

Gnomad4 AFR exome

AF:

0.437

Gnomad4 AMR exome

AF:

0.130

Gnomad4 ASJ exome

AF:

0.0821

Gnomad4 EAS exome

AF:

0.0654

Gnomad4 SAS exome

AF:

0.0686

Gnomad4 FIN exome

AF:

0.0727

Gnomad4 NFE exome

AF:

0.0718

Gnomad4 OTH exome

AF:

0.0974

GnomAD4 genome

AF:

0.176

AC:

26733

AN:

152000

Hom.:

4209

Cov.:

AF XY:

0.172

AC XY:

12796

AN XY:

74278

show subpopulations

Gnomad4 AFR

AF:

0.424

Gnomad4 AMR

AF:

0.126

Gnomad4 ASJ

AF:

0.0862

Gnomad4 EAS

AF:

0.0607

Gnomad4 SAS

AF:

0.0616

Gnomad4 FIN

AF:

0.0836

Gnomad4 NFE

AF:

0.0735

Gnomad4 OTH

AF:

0.161

Alfa

AF:

0.0677

Hom.:

162

Bravo

AF:

0.191

TwinsUK

AF:

0.0669

AC:

248

ALSPAC

AF:

0.0716

AC:

276

ESP6500AA

AF:

0.375

AC:

1631

ESP6500EA

AF:

0.0667

AC:

567

ExAC

AF:

0.0827

AC:

9471

Asia WGS

AF:

0.108

AC:

374

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 09, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

0.58

DANN

Benign

0.58

Eigen

Benign

-2.4

Eigen_PC

Benign

-2.4

FATHMM_MKL

Benign

0.0070

LIST_S2

Benign

0.23

T;.;T;.

MetaRNN

Benign

0.00014

T;T;T;T

MetaSVM

Benign

-0.99

MutationTaster

Benign

1.0

P;P;P;P;P

PrimateAI

Benign

0.27

Polyphen

0.0

B;.;.;B

Vest4

0.029

MPC

0.37

ClinPred

0.0033

GERP RS

-2.6

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over