Variant chr15-45135494-G-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_175940.3(DUOX1):c.516G>T(p.Trp172Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000514 in 1,555,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000043 ( 0 hom. )

Consequence

DUOX1
NM_175940.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.67

Variant links:

Genes affected

DUOX1 (HGNC:3062): (dual oxidase 1) 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 proteins encoded by this gene and the similar DUOX2 gene. This protein is known as dual oxidase because it has both a peroxidase homology domain and a gp91phox domain. This protein generates hydrogen peroxide and thereby plays a role in the activity of thyroid peroxidase, lactoperoxidase, and in lactoperoxidase-mediated antimicrobial defense at mucosal surfaces. Two alternatively spliced transcript variants encoding the same protein have been described for this gene. [provided by RefSeq, Jul 2012]

DUOX1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3 linkuse as main transcript	c.516G>T	p.Trp172Cys	missense_variant	6/34	ENST00000389037.7	NP_787954.1	Q9NRD9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOX1	ENST00000389037.7 linkuse as main transcript	c.516G>T	p.Trp172Cys	missense_variant	6/34	1	NM_175940.3	ENSP00000373689.3	Q9NRD9-1
DUOX1	ENST00000321429.8 linkuse as main transcript	c.516G>T	p.Trp172Cys	missense_variant	7/35	1		ENSP00000317997.4	Q9NRD9-1
DUOX1	ENST00000561220.6 linkuse as main transcript	n.516G>T		non_coding_transcript_exon_variant	6/33	5		ENSP00000452623.1	H0YK19

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152278

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000428

AC:

AN:

1403498

Hom.:

Cov.:

AF XY:

0.00000433

AC XY:

AN XY:

693254

show subpopulations

Gnomad4 AFR exome

AF:

0.000125

Gnomad4 AMR exome

AF:

0.0000271

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000172

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152278

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74392

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000227

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 04, 2024

The c.516G>T (p.W172C) alteration is located in exon 7 (coding exon 5) of the DUOX1 gene. This alteration results from a G to T substitution at nucleotide position 516, causing the tryptophan (W) at amino acid position 172 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.38

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.56

D;D

Eigen

Pathogenic

0.75

Eigen_PC

Uncertain

0.63

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.97

.;D

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.97

D;D

MetaSVM

Uncertain

0.23

MutationAssessor

Pathogenic

3.0

M;M

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-9.7

D;D

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.87

Gain of disorder (P = 0.1009);Gain of disorder (P = 0.1009);

MVP

0.93

MPC

1.3

ClinPred

1.0

GERP RS

3.8

Varity_R

0.97

gMVP

0.86

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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