15-45135588-G-A

Position:

• chr15-45135588-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.610G>A​(p.Ala204Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000425 in 1,411,588 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.36

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=0.17141137).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOX1	NM_175940.3	c.610G>A	p.Ala204Thr	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.610G>A	p.Ala204Thr	missense_variant	6/34	1	NM_175940.3	ENSP00000373689.3
DUOX1	ENST00000321429.8	c.610G>A	p.Ala204Thr	missense_variant	7/35	1		ENSP00000317997.4
DUOX1	ENST00000561220.6	n.610G>A		non_coding_transcript_exon_variant	6/33	5		ENSP00000452623.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000425 AC: 6 AN: 1411588 Hom.: 0 Cov.: 34 AF XY: 0.00000717 AC XY: 5 AN XY: 697822

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: 0.00000552

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

Apr 27, 2022

The c.610G>A (p.A204T) alteration is located in exon 7 (coding exon 5) of the DUOX1 gene. This alteration results from a G to A substitution at nucleotide position 610, causing the alanine (A) at amino acid position 204 to be replaced by a threonine (T). 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	0.091
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.063	T;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.076	N
LIST_S2	Benign	0.77	.;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.4	L;L
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.70	N;N
REVEL	Benign	0.14
Sift	Benign	0.35	T;T
Sift4G	Benign	0.37	T;T
Polyphen		0.81	P;P
Vest4		0.19
MutPred		0.28		Gain of phosphorylation at A204 (P = 0.0134);Gain of phosphorylation at A204 (P = 0.0134);
MVP		0.83
MPC		0.31
ClinPred		0.33	T
GERP RS		3.9
Varity_R		0.12
gMVP		0.27

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: chr15-45427786;