15-45135133-G-A

Position:

• chr15-45135133-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_175940.3(DUOX1):​c.337G>A​(p.Val113Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,613,702 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.583

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1187495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3	c.337G>A	p.Val113Met	missense_variant	5/34	ENST00000389037.7	NP_787954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX1	ENST00000389037.7	c.337G>A	p.Val113Met	missense_variant	5/34	1	NM_175940.3	ENSP00000373689.3
DUOX1	ENST00000321429.8	c.337G>A	p.Val113Met	missense_variant	6/35	1		ENSP00000317997.4
DUOX1	ENST00000561220.6	n.337G>A		non_coding_transcript_exon_variant	5/33	5		ENSP00000452623.1

Frequencies

GnomAD3 genomes AF: 0.0000789 AC: 12 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000481 AC: 12 AN: 249584 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135126

Gnomad AFR exome AF: 0.0000617

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.000498

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000981

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1461420 Hom.: 0 Cov.: 32 AF XY: 0.0000413 AC XY: 30 AN XY: 727024

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.000651

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.000149

GnomAD4 genome AF: 0.0000722 AC: 11 AN: 152282 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74454

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000900 Hom.: 0

Bravo AF: 0.0000718

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

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

May 10, 2022

The c.337G>A (p.V113M) alteration is located in exon 6 (coding exon 4) of the DUOX1 gene. This alteration results from a G to A substitution at nucleotide position 337, causing the valine (V) at amino acid position 113 to be replaced by a methionine (M). 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	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.088	T;T
Eigen	Benign	-0.20
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.81	.;T
M_CAP	Benign	0.031	D
MetaRNN	Benign	0.12	T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.16
Sift	Benign	0.059	T;T
Sift4G	Uncertain	0.035	D;D
Polyphen		0.87	P;P
Vest4		0.38
MVP		0.78
MPC		0.73
ClinPred		0.12	T
GERP RS		1.0
Varity_R		0.097
gMVP		0.52

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: rs377251160; hg19: chr15-45427331;