15-45153958-C-T

Position:

• chr15-45153958-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_175940.3(DUOX1):​c.3532C>T​(p.Leu1178Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.653 in 1,608,952 control chromosomes in the GnomAD database, including 348,393 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.59 (27050 hom., cov: 29)
  • Exomes 𝑓: 0.66 (321343 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.584

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.4798455E-6).
• BP6: Variant 15-45153958-C-T is Benign according to our data. Variant chr15-45153958-C-T is described in ClinVar as [Benign]. Clinvar id is 1301432.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.697 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3	c.3532C>T	p.Leu1178Phe	missense_variant	27/34	ENST00000389037.7	NP_787954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX1	ENST00000389037.7	c.3532C>T	p.Leu1178Phe	missense_variant	27/34	1	NM_175940.3	ENSP00000373689.3

Frequencies

GnomAD3 genomes AF: 0.586 AC: 88706 AN: 151438 Hom.: 27054 Cov.: 29

Gnomad AFR AF: 0.417

Gnomad AMI AF: 0.803

Gnomad AMR AF: 0.580

Gnomad ASJ AF: 0.585

Gnomad EAS AF: 0.476

Gnomad SAS AF: 0.718

Gnomad FIN AF: 0.659

Gnomad MID AF: 0.611

Gnomad NFE AF: 0.673

Gnomad OTH AF: 0.602

GnomAD3 exomes AF: 0.619 AC: 155532 AN: 251390 Hom.: 49469 AF XY: 0.632 AC XY: 85935 AN XY: 135878

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.503

Gnomad ASJ exome AF: 0.592

Gnomad EAS exome AF: 0.480

Gnomad SAS exome AF: 0.708

Gnomad FIN exome AF: 0.659

Gnomad NFE exome AF: 0.676

Gnomad OTH exome AF: 0.638

GnomAD4 exome AF: 0.660 AC: 962361 AN: 1457398 Hom.: 321343 Cov.: 40 AF XY: 0.662 AC XY: 480428 AN XY: 725294

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.509

Gnomad4 ASJ exome AF: 0.589

Gnomad4 EAS exome AF: 0.494

Gnomad4 SAS exome AF: 0.704

Gnomad4 FIN exome AF: 0.657

Gnomad4 NFE exome AF: 0.680

Gnomad4 OTH exome AF: 0.636

GnomAD4 genome AF: 0.585 AC: 88725 AN: 151554 Hom.: 27050 Cov.: 29 AF XY: 0.589 AC XY: 43574 AN XY: 73992

Gnomad4 AFR AF: 0.417

Gnomad4 AMR AF: 0.580

Gnomad4 ASJ AF: 0.585

Gnomad4 EAS AF: 0.476

Gnomad4 SAS AF: 0.717

Gnomad4 FIN AF: 0.659

Gnomad4 NFE AF: 0.673

Gnomad4 OTH AF: 0.600

Alfa AF: 0.649 Hom.: 64676

Bravo AF: 0.567

TwinsUK AF: 0.683 AC: 2534

ALSPAC AF: 0.683 AC: 2632

ESP6500AA AF: 0.425 AC: 1870

ESP6500EA AF: 0.676 AC: 5814

ExAC AF: 0.625 AC: 75835

Asia WGS AF: 0.610 AC: 2125 AN: 3478

EpiCase AF: 0.671

EpiControl AF: 0.669

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.043
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.46	N
LIST_S2	Benign	0.036	.;T;T
MetaRNN	Benign	0.0000025	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.63	N;N;.
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.42	N;N;N
REVEL	Benign	0.12
Sift	Benign	0.44	T;T;T
Sift4G	Benign	0.25	T;T;T
Polyphen		0.0020	B;B;.
Vest4		0.078
MPC		0.32
ClinPred		0.0057	T
GERP RS		3.4
Varity_R		0.041
gMVP		0.15

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

Other links and lift over

dbSNP: rs2458236; hg19: chr15-45446156; COSMIC: COSV58478086; COSMIC: COSV58478086;