chr15-45135534-A-G

Position:

• chr15-45135534-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_175940.3(DUOX1):​c.556A>G​(p.Ser186Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000355 in 1,407,320 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.40

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3	c.556A>G	p.Ser186Gly	missense_variant	6/34	ENST00000389037.7	NP_787954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX1	ENST00000389037.7	c.556A>G	p.Ser186Gly	missense_variant	6/34	1	NM_175940.3	ENSP00000373689.3
DUOX1	ENST00000321429.8	c.556A>G	p.Ser186Gly	missense_variant	7/35	1		ENSP00000317997.4
DUOX1	ENST00000561220.6	n.556A>G		non_coding_transcript_exon_variant	6/33	5		ENSP00000452623.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000355 AC: 5 AN: 1407320 Hom.: 0 Cov.: 33 AF XY: 0.00000431 AC XY: 3 AN XY: 695408

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00000461

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 26, 2024

The c.556A>G (p.S186G) alteration is located in exon 7 (coding exon 5) of the DUOX1 gene. This alteration results from a A to G substitution at nucleotide position 556, causing the serine (S) at amino acid position 186 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Uncertain	0.031	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	27
DANN	Benign	0.97
DEOGEN2	Benign	0.34	T;T
Eigen	Benign	0.15
Eigen_PC	Benign	0.014
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.94	.;D
M_CAP	Pathogenic	0.31	D
MetaRNN	Uncertain	0.72	D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Pathogenic	3.0	M;M
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.034	D;D
Polyphen		0.95	P;P
Vest4		0.59
MutPred		0.63		Loss of phosphorylation at S186 (P = 0.0618);Loss of phosphorylation at S186 (P = 0.0618);
MVP		0.86
MPC		0.63
ClinPred		0.95	D
GERP RS		2.8
Varity_R		0.56
gMVP		0.60

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-45427732;