NM_175940.3:c.3532C>A

Variant names:

• chr15-45153958-C-A
• rs2458236
• NM_175940.3:c.3532C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175940.3(DUOX1):​c.3532C>A​(p.Leu1178Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,612,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L1178F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.584
• Publications: 41 publications found

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]

ENSG00000259539 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13894361).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_175940.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX1	NM_175940.3	MANE Select	c.3532C>A	p.Leu1178Ile	missense	Exon 27 of 34	NP_787954.1
	DUOX1	NM_017434.5		c.3532C>A	p.Leu1178Ile	missense	Exon 28 of 35	NP_059130.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOX1	ENST00000389037.7	TSL:1 MANE Select	c.3532C>A	p.Leu1178Ile	missense	Exon 27 of 34	ENSP00000373689.3
	DUOX1	ENST00000321429.8	TSL:1	c.3532C>A	p.Leu1178Ile	missense	Exon 28 of 35	ENSP00000317997.4
	DUOX1	ENST00000885347.1		c.3532C>A	p.Leu1178Ile	missense	Exon 26 of 33	ENSP00000555406.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151536 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000119 AC: 3 AN: 251390 AF XY: 0.0000221

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000178 AC: 26 AN: 1460594 Hom.: 0 Cov.: 40 AF XY: 0.0000206 AC XY: 15 AN XY: 726702

African (AFR) AF: 0.0000299 AC: 1 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26110

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.0000198 AC: 22 AN: 1110866

Other (OTH) AF: 0.00 AC: 0 AN: 60352

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151536 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 73932

African (AFR) AF: 0.00 AC: 0 AN: 41168

American (AMR) AF: 0.0000656 AC: 1 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10428

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67940

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 87523

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.13	T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.14	T
MetaSVM	Uncertain	-0.068	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.58
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-0.61	N
REVEL	Benign	0.21
Sift	Benign	0.084	T
Sift4G	Benign	0.077	T
Polyphen		0.0060	B
Vest4		0.22
MutPred		0.41		Loss of catalytic residue at L1178 (P = 0.0325)
MVP		0.78
MPC		0.32
ClinPred		0.21	T
GERP RS		3.4
Varity_R		0.057
gMVP		0.20
Mutation Taster		=90/10	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2458236; hg19: chr15-45446156;