15-45134148-C-T

Variant names:

• chr15-45134148-C-T
• NM_175940.3:c.146C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_175940.3(DUOX1):​c.146C>T​(p.Ser49Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DUOX1 NM_175940.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33228558).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOX1	NM_175940.3	c.146C>T	p.Ser49Phe	missense_variant	Exon 4 of 34	ENST00000389037.7	NP_787954.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOX1	ENST00000389037.7	c.146C>T	p.Ser49Phe	missense_variant	Exon 4 of 34	1	NM_175940.3	ENSP00000373689.3
DUOX1	ENST00000321429.8	c.146C>T	p.Ser49Phe	missense_variant	Exon 5 of 35	1		ENSP00000317997.4
DUOX1	ENST00000561220.6	n.146C>T		non_coding_transcript_exon_variant	Exon 4 of 33	5		ENSP00000452623.1
DUOX1	ENST00000558322.5	c.*214C>T		downstream_gene_variant		2		ENSP00000454121.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.146C>T (p.S49F) alteration is located in exon 5 (coding exon 3) of the DUOX1 gene. This alteration results from a C to T substitution at nucleotide position 146, causing the serine (S) at amino acid position 49 to be replaced by a phenylalanine (F). 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	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.092
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.73	.;T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.33	T;T
MetaSVM	Benign	-0.67	T
MutationAssessor	Uncertain	2.2	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-3.3	D;D
REVEL	Uncertain	0.44
Sift	Benign	0.50	T;T
Sift4G	Benign	0.32	T;T
Polyphen		0.0060	B;B
Vest4		0.38
MutPred		0.65		Loss of disorder (P = 0.0125);Loss of disorder (P = 0.0125);
MVP		0.82
MPC		0.36
ClinPred		0.73	D
GERP RS		4.1
Varity_R		0.52
gMVP		0.73

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: chr15-45426346;