15-45114683-C-G

Position:

• chr15-45114683-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_207581.4(DUOXA2):​c.78C>G​(p.Ile26Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DUOXA2 NM_207581.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.87

Genes affected

DUOXA2 (HGNC:32698): (dual oxidase maturation factor 2) This gene encodes an endoplasmic reticulum protein that is necessary for proper cellular localization and maturation of functional dual oxidase 2. Mutations in this gene have been associated with thyroid dyshormonogenesis 5.[provided by RefSeq, Feb 2010]

DUOXA2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.75

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOXA2	NM_207581.4	c.78C>G	p.Ile26Met	missense_variant	1/6	ENST00000323030.6	NP_997464.2
DUOXA2	XM_017022180.2	c.78C>G	p.Ile26Met	missense_variant	1/6		XP_016877669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DUOXA2	ENST00000323030.6	c.78C>G	p.Ile26Met	missense_variant	1/6	1	NM_207581.4	ENSP00000319705.5
DUOXA2	ENST00000491993.2	n.78C>G		non_coding_transcript_exon_variant	1/6	1		ENSP00000454110.1
DUOXA2	ENST00000350243.10	n.358C>G		non_coding_transcript_exon_variant	1/5	2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727246

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Nov 20, 2023

Variant summary: DUOXA2 c.78C>G (p.Ile26Met) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251416 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.78C>G has been reported in the literature as a single heterozygous change in one individual affected with Congenital Goiter Hypothyroidism (example, Liu_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Thyroglobulin synthesis defect. At least one publication reports experimental evidence evaluating an impact on protein function, however, DUOXA2 and DUOX2 expression levels in HeLa cells are not affected by this variant, whereas H2O2 generation assays confirmed defects of NADPH oxidase activity. As no direct effect on DUOXA2 function has been performed, this study does not allow convincing conclusions about the variant effect (Liu_2015). The following publication have been ascertained in the context of this evaluation (PMID: 25675383). No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.053	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.78	T
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Benign	-0.75	T
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	-0.98	N
REVEL	Pathogenic	0.70
Sift	Benign	0.038	D
Sift4G	Uncertain	0.032	D
Polyphen		0.99	D
Vest4		0.72
MutPred		0.57		Loss of sheet (P = 0.0457);
MVP		0.54
MPC		0.70
ClinPred		0.80	D
GERP RS		-6.0
Varity_R		0.13
gMVP		0.90

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: chr15-45406881;