15-45117274-C-T

Variant names:

• chr15-45117274-C-T
• rs4774518
• NM_207581.4:c.738C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_207581.4(DUOXA2):​c.738C>T​(p.Tyr246Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,603,938 control chromosomes in the GnomAD database, including 223 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (28 hom., cov: 33)
  • Exomes 𝑓: 0.011 (195 hom.)
• Consequence: DUOXA2 NM_207581.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77
• Publications: 40 publications found

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]

DUOXA1 (HGNC:26507): (dual oxidase maturation factor 1) Dual oxidases DUOX1 and DUOX2 are NADPH oxidases which are involved in hydrogen peroxide production necessary for thyroid hormonogenesis. They form a heterodimer with specific maturation factors DUOXA1 and DUOXA2, respectively, which is essential for the maturation and function of the DUOX enzyme complexes. This gene encodes the DUOX1 activator or maturation factor DUOXA1. Rat studies identified a bidirectional promoter which controls the transcription of the DUOX1 and DUOXA1 genes. This protein is cotransported to the cell surface when coexpressed with DUOX1 and is retained in the endoplasmic reticulum when expressed without DUOX1 protein. The expression of this gene or the DUOX1 gene is not suppressed by thyroglobulin (Tg), a macromolecular precursor in thyroid hormone synthesis, while the expression of the DUOX2 and DUOXA2 are significantly suppressed by the Tg. This protein is also a p53-regulated neurogenic factor involved in p53 dependent neuronal differentiation. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2013]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 15-45117274-C-T is Benign according to our data. Variant chr15-45117274-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293942.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0508 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_207581.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	NM_207581.4	MANE Select	c.738C>T	p.Tyr246Tyr	synonymous	Exon 5 of 6	NP_997464.2	Q1HG44-1
	DUOXA1	NM_001276266.2	MANE Select	c.*1832G>A		downstream_gene	N/A	NP_001263195.1	B5M0B7
	DUOXA1	NM_001276264.2		c.*241G>A		downstream_gene	N/A	NP_001263193.1	Q1HG43-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	ENST00000323030.6	TSL:1 MANE Select	c.738C>T	p.Tyr246Tyr	synonymous	Exon 5 of 6	ENSP00000319705.5	Q1HG44-1
	DUOXA2	ENST00000491993.2	TSL:1	n.*805C>T		non_coding_transcript_exon	Exon 5 of 6	ENSP00000454110.1	Q1HG44-2
	DUOXA2	ENST00000491993.2	TSL:1	n.*805C>T		3_prime_UTR	Exon 5 of 6	ENSP00000454110.1	Q1HG44-2

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1936 AN: 152236 Hom.: 27 Cov.: 33

Gnomad AFR AF: 0.0106

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0204

Gnomad ASJ AF: 0.00461

Gnomad EAS AF: 0.0565

Gnomad SAS AF: 0.00807

Gnomad FIN AF: 0.0121

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00916

Gnomad OTH AF: 0.0138

GnomAD2 exomes AF: 0.0169 AC: 4019 AN: 237622 AF XY: 0.0154

Gnomad AFR exome AF: 0.0102

Gnomad AMR exome AF: 0.0378

Gnomad ASJ exome AF: 0.00280

Gnomad EAS exome AF: 0.0539

Gnomad FIN exome AF: 0.00883

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.0141

GnomAD4 exome AF: 0.0111 AC: 16121 AN: 1451584 Hom.: 195 Cov.: 33 AF XY: 0.0108 AC XY: 7797 AN XY: 720750

African (AFR) AF: 0.0107 AC: 357 AN: 33330

American (AMR) AF: 0.0345 AC: 1529 AN: 44258

Ashkenazi Jewish (ASJ) AF: 0.00278 AC: 72 AN: 25856

East Asian (EAS) AF: 0.0617 AC: 2436 AN: 39474

South Asian (SAS) AF: 0.00759 AC: 649 AN: 85482

European-Finnish (FIN) AF: 0.00971 AC: 496 AN: 51102

Middle Eastern (MID) AF: 0.00387 AC: 22 AN: 5678

European-Non Finnish (NFE) AF: 0.00889 AC: 9837 AN: 1106502

Other (OTH) AF: 0.0121 AC: 723 AN: 59902

GnomAD4 genome AF: 0.0128 AC: 1945 AN: 152354 Hom.: 28 Cov.: 33 AF XY: 0.0131 AC XY: 978 AN XY: 74494

African (AFR) AF: 0.0107 AC: 445 AN: 41594

American (AMR) AF: 0.0204 AC: 313 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00461 AC: 16 AN: 3470

East Asian (EAS) AF: 0.0561 AC: 290 AN: 5170

South Asian (SAS) AF: 0.00870 AC: 42 AN: 4828

European-Finnish (FIN) AF: 0.0121 AC: 129 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00916 AC: 623 AN: 68036

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.00942 Hom.: 14

Bravo AF: 0.0139

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	0.34
DANN	Benign	0.85
PhyloP100		-1.8
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4774518; hg19: chr15-45409472;