chr15-45135594-C-T

Variant names:

• chr15-45135594-C-T
• rs780226181
• NM_175940.3:c.616C>T

Variant summary

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

The NM_175940.3(DUOX1):​c.616C>T​(p.Pro206Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000708 in 1,412,282 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P206T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.27
• Publications: 0 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]

ENSG00000300788 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.616C>T	p.Pro206Ser	missense	Exon 6 of 34	NP_787954.1	Q9NRD9-1
	DUOX1	NM_017434.5		c.616C>T	p.Pro206Ser	missense	Exon 7 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.616C>T	p.Pro206Ser	missense	Exon 6 of 34	ENSP00000373689.3	Q9NRD9-1
	DUOX1	ENST00000321429.8	TSL:1	c.616C>T	p.Pro206Ser	missense	Exon 7 of 35	ENSP00000317997.4	Q9NRD9-1
	DUOX1	ENST00000885347.1		c.616C>T	p.Pro206Ser	missense	Exon 5 of 33	ENSP00000555406.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.08e-7 AC: 1 AN: 1412282 Hom.: 0 Cov.: 34 AF XY: 0.00000143 AC XY: 1 AN XY: 698250

African (AFR) AF: 0.00 AC: 0 AN: 32502

American (AMR) AF: 0.00 AC: 0 AN: 37720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25288

East Asian (EAS) AF: 0.00 AC: 0 AN: 37220

South Asian (SAS) AF: 0.00 AC: 0 AN: 80788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4222

European-Non Finnish (NFE) AF: 9.19e-7 AC: 1 AN: 1087782

Other (OTH) AF: 0.00 AC: 0 AN: 58360

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.77
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Pathogenic	0.68
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.90	D
M_CAP	Uncertain	0.19	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.38	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		7.3
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.51
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.54
MutPred		0.49		Gain of phosphorylation at P206 (P = 0.0647)
MVP		0.92
MPC		1.0
ClinPred		0.99	D
GERP RS		3.9
Varity_R		0.72
gMVP		0.55
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs780226181; hg19: chr15-45427792;