Variant 15-45135935-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_175940.3(DUOX1):c.851T>C(p.Ile284Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000303 in 1,322,032 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00051 ( 0 hom., cov: 29)

Exomes 𝑓: 0.00030 ( 1 hom. )

Failed GnomAD Quality Control

Consequence

DUOX1
NM_175940.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.66

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_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.15573686).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3 linkuse as main transcript	c.851T>C	p.Ile284Thr	missense_variant	7/34	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.851T>C	p.Ile284Thr	missense_variant	7/34	1	NM_175940.3	ENSP00000373689.3	Q9NRD9-1
DUOX1	ENST00000321429.8 linkuse as main transcript	c.851T>C	p.Ile284Thr	missense_variant	8/35	1		ENSP00000317997.4	Q9NRD9-1
DUOX1	ENST00000561220.6 linkuse as main transcript	n.851T>C		non_coding_transcript_exon_variant	7/33	5		ENSP00000452623.1	H0YK19

Frequencies

GnomAD3 genomes

AF:

0.000508

AC:

AN:

149572

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000992

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00273

Gnomad ASJ

AF:

0.000868

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000439

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000326

Gnomad OTH

AF:

0.000978

GnomAD3 exomes

AF:

0.000383

AC:

AN:

86092

Hom.:

AF XY:

0.000376

AC XY:

AN XY:

45164

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00111

Gnomad ASJ exome

AF:

0.000838

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000169

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000281

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000303

AC:

400

AN:

1322032

Hom.:

Cov.:

AF XY:

0.000309

AC XY:

202

AN XY:

652934

show subpopulations

Gnomad4 AFR exome

AF:

0.000265

Gnomad4 AMR exome

AF:

0.000715

Gnomad4 ASJ exome

AF:

0.000917

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000446

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000255

Gnomad4 OTH exome

AF:

0.000597

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000508

AC:

AN:

149686

Hom.:

Cov.:

AF XY:

0.000671

AC XY:

AN XY:

72994

show subpopulations

Gnomad4 AFR

AF:

0.0000989

Gnomad4 AMR

AF:

0.00272

Gnomad4 ASJ

AF:

0.000868

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000440

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000326

Gnomad4 OTH

AF:

0.000967

Alfa

AF:

0.000529

Hom.:

Bravo

AF:

0.000468

ExAC

AF:

0.000137

AC:

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

May 16, 2023

The c.851T>C (p.I284T) alteration is located in exon 8 (coding exon 6) of the DUOX1 gene. This alteration results from a T to C substitution at nucleotide position 851, causing the isoleucine (I) at amino acid position 284 to be replaced by a threonine (T). 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

Benign

0.22

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

T;T

Eigen

Pathogenic

0.68

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.85

.;T

M_CAP

Benign

0.064

MetaRNN

Benign

0.16

T;T

MetaSVM

Uncertain

0.049

MutationAssessor

Benign

1.9

L;L

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.71

Sift

Uncertain

0.0010

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.99

D;D

Vest4

0.62

MutPred

0.77

Loss of methylation at K281 (P = 0.0425);Loss of methylation at K281 (P = 0.0425);

MVP

0.93

MPC

0.55

ClinPred

0.14

GERP RS

4.3

Varity_R

0.76

gMVP

0.32

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