NM_207581.4:c.555-18C>T

Variant names:

• chr15-45117073-C-T
• rs955152
• NM_207581.4:c.555-18C>T

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.555-18C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.868 in 1,596,472 control chromosomes in the GnomAD database, including 618,797 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (45200 hom., cov: 36)
  • Exomes 𝑓: 0.88 (573597 hom.)
• Consequence: DUOXA2 NM_207581.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.77
• Publications: 10 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=-0.91).
• BP6: Variant 15-45117073-C-T is Benign according to our data. Variant chr15-45117073-C-T is described in ClinVar as Benign. ClinVar VariationId is 263306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.897 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.555-18C>T		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.555-18C>T		intron	N/A	ENSP00000319705.5
	DUOXA2	ENST00000491993.2	TSL:1	n.*622-18C>T		intron	N/A	ENSP00000454110.1
	DUOXA2	ENST00000350243.10	TSL:2	n.1178C>T		non_coding_transcript_exon	Exon 4 of 5

Frequencies

GnomAD3 genomes AF: 0.711 AC: 108226 AN: 152158 Hom.: 45213 Cov.: 36

Gnomad AFR AF: 0.235

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.834

Gnomad ASJ AF: 0.891

Gnomad EAS AF: 0.866

Gnomad SAS AF: 0.910

Gnomad FIN AF: 0.911

Gnomad MID AF: 0.848

Gnomad NFE AF: 0.903

Gnomad OTH AF: 0.763

GnomAD2 exomes AF: 0.851 AC: 193876 AN: 227768 AF XY: 0.864

Gnomad AFR exome AF: 0.220

Gnomad AMR exome AF: 0.852

Gnomad ASJ exome AF: 0.898

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.920

Gnomad NFE exome AF: 0.905

Gnomad OTH exome AF: 0.881

GnomAD4 exome AF: 0.885 AC: 1277560 AN: 1444196 Hom.: 573597 Cov.: 50 AF XY: 0.888 AC XY: 638203 AN XY: 718848

African (AFR) AF: 0.213 AC: 7100 AN: 33390

American (AMR) AF: 0.846 AC: 37723 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.899 AC: 23469 AN: 26098

East Asian (EAS) AF: 0.859 AC: 33995 AN: 39554

South Asian (SAS) AF: 0.908 AC: 78072 AN: 85966

European-Finnish (FIN) AF: 0.919 AC: 35065 AN: 38152

Middle Eastern (MID) AF: 0.886 AC: 4594 AN: 5184

European-Non Finnish (NFE) AF: 0.905 AC: 1005884 AN: 1111134

Other (OTH) AF: 0.859 AC: 51658 AN: 60140

GnomAD4 genome AF: 0.711 AC: 108211 AN: 152276 Hom.: 45200 Cov.: 36 AF XY: 0.720 AC XY: 53607 AN XY: 74464

African (AFR) AF: 0.234 AC: 9723 AN: 41538

American (AMR) AF: 0.834 AC: 12774 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.891 AC: 3092 AN: 3472

East Asian (EAS) AF: 0.866 AC: 4475 AN: 5168

South Asian (SAS) AF: 0.910 AC: 4394 AN: 4830

European-Finnish (FIN) AF: 0.911 AC: 9681 AN: 10622

Middle Eastern (MID) AF: 0.844 AC: 248 AN: 294

European-Non Finnish (NFE) AF: 0.903 AC: 61402 AN: 68016

Other (OTH) AF: 0.759 AC: 1605 AN: 2116

Alfa AF: 0.800 Hom.: 9706

Bravo AF: 0.684

Asia WGS AF: 0.804 AC: 2798 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.085
DANN	Benign	0.82
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: rs955152; hg19: chr15-45409271;