15-45136534-C-T

Position:

• chr15-45136534-C-T

Variant summary

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

The NM_175940.3(DUOX1):​c.931C>T​(p.Arg311Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.12

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.931C>T	p.Arg311Trp	missense_variant	9/34	ENST00000389037.7	NP_787954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOX1	ENST00000389037.7	c.931C>T	p.Arg311Trp	missense_variant	9/34	1	NM_175940.3	ENSP00000373689.3
DUOX1	ENST00000321429.8	c.931C>T	p.Arg311Trp	missense_variant	10/35	1		ENSP00000317997.4
DUOX1	ENST00000561220.6	n.931C>T		non_coding_transcript_exon_variant	9/33	5		ENSP00000452623.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

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

May 08, 2024

The c.931C>T (p.R311W) alteration is located in exon 10 (coding exon 8) of the DUOX1 gene. This alteration results from a C to T substitution at nucleotide position 931, causing the arginine (R) at amino acid position 311 to be replaced by a tryptophan (W). 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	0.13
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T
Eigen	Benign	-0.034
Eigen_PC	Benign	-0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	.;D
M_CAP	Benign	0.082	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Uncertain	2.5	M;M
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Uncertain	0.39
Sift	Uncertain	0.0060	D;D
Sift4G	Uncertain	0.010	D;D
Polyphen		0.99	D;D
Vest4		0.51
MutPred		0.56		Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);
MVP		0.88
MPC		0.76
ClinPred		0.98	D
GERP RS		1.7
Varity_R		0.26
gMVP		0.41

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: chr15-45428732;