15-45116512-A-G

Variant names:

• chr15-45116512-A-G
• rs2554459
• NM_207581.4:c.341-4A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_207581.4(DUOXA2):​c.341-4A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.989 in 1,613,584 control chromosomes in the GnomAD database, including 790,660 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.94 (67845 hom., cov: 33)
  • Exomes 𝑓: 0.99 (722815 hom.)
• Consequence: DUOXA2 NM_207581.4 splice_region, intron
• Scores: Splicing: ADA: 0.0002449
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.380
• Publications: 11 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]

DUOXA2 Gene-Disease associations (from GenCC):

• thyroid dyshormonogenesis 5

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 15-45116512-A-G is Benign according to our data. Variant chr15-45116512-A-G is described in ClinVar as Benign. ClinVar VariationId is 263304.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.993 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	NM_207581.4	MANE Select	c.341-4A>G		splice_region intron	N/A	NP_997464.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	ENST00000323030.6	TSL:1 MANE Select	c.341-4A>G		splice_region intron	N/A	ENSP00000319705.5
	DUOXA2	ENST00000491993.2	TSL:1	n.*408-4A>G		splice_region intron	N/A	ENSP00000454110.1
	DUOXA2	ENST00000350243.10	TSL:2	n.621-4A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.939 AC: 142920 AN: 152158 Hom.: 67809 Cov.: 33

Gnomad AFR AF: 0.787

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.981

Gnomad ASJ AF: 1.00

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.999

Gnomad OTH AF: 0.962

GnomAD2 exomes AF: 0.985 AC: 245352 AN: 248988 AF XY: 0.989

Gnomad AFR exome AF: 0.787

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 1.00

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.995

GnomAD4 exome AF: 0.994 AC: 1452648 AN: 1461308 Hom.: 722815 Cov.: 59 AF XY: 0.995 AC XY: 723338 AN XY: 726990

African (AFR) AF: 0.788 AC: 26370 AN: 33472

American (AMR) AF: 0.991 AC: 44321 AN: 44724

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 26135 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39700 AN: 39700

South Asian (SAS) AF: 1.00 AC: 86233 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 52864 AN: 52864

Middle Eastern (MID) AF: 0.994 AC: 5733 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111646 AN: 1111998

Other (OTH) AF: 0.988 AC: 59646 AN: 60390

GnomAD4 genome AF: 0.939 AC: 143016 AN: 152276 Hom.: 67845 Cov.: 33 AF XY: 0.943 AC XY: 70190 AN XY: 74472

African (AFR) AF: 0.787 AC: 32676 AN: 41528

American (AMR) AF: 0.981 AC: 15017 AN: 15304

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 3472 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5166 AN: 5166

South Asian (SAS) AF: 1.00 AC: 4822 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10628 AN: 10628

Middle Eastern (MID) AF: 0.986 AC: 288 AN: 292

European-Non Finnish (NFE) AF: 0.999 AC: 68000 AN: 68036

Other (OTH) AF: 0.963 AC: 2035 AN: 2114

Alfa AF: 0.977 Hom.: 66112

Bravo AF: 0.932

Asia WGS AF: 0.987 AC: 3433 AN: 3478

EpiCase AF: 0.999

EpiControl AF: 0.999

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Thyroglobulin synthesis defect Benign:1

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.4
DANN	Benign	0.38
PhyloP100		-0.38
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00024
dbscSNV1_RF	Benign	0.0060
SpliceAI score (max)		0.070		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: rs2554459; hg19: chr15-45408710;