NM_207581.4:c.554+6T>C

Variant names:

• chr15-45116735-T-C
• rs2576092
• NM_207581.4:c.554+6T>C

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.554+6T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 1,612,548 control chromosomes in the GnomAD database, including 654,719 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 0.77 (49337 hom., cov: 34)
  • Exomes 𝑓: 0.91 (605382 hom.)
• Consequence: DUOXA2 NM_207581.4 splice_region, intron
• Scores: Splicing: ADA: 0.007383
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.44
• 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=-0.84).
• BP6: Variant 15-45116735-T-C is Benign according to our data. Variant chr15-45116735-T-C is described in CliVar as Benign. Clinvar id is 263305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45116735-T-C is described in CliVar as Benign. Clinvar id is 263305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr15-45116735-T-C is described in CliVar as Benign. Clinvar id is 263305.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.916 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DUOXA2	NM_207581.4	c.554+6T>C		splice_region_variant, intron_variant	Intron 4 of 5	ENST00000323030.6	NP_997464.2
DUOXA2	XM_017022180.2	c.605+6T>C		splice_region_variant, intron_variant	Intron 4 of 5		XP_016877669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DUOXA2	ENST00000323030.6	c.554+6T>C		splice_region_variant, intron_variant	Intron 4 of 5	1	NM_207581.4	ENSP00000319705.5
DUOXA2	ENST00000491993.2	n.*621+6T>C		splice_region_variant, intron_variant	Intron 4 of 5	1		ENSP00000454110.1
DUOXA2	ENST00000350243.10	n.840T>C		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes AF: 0.773 AC: 117438 AN: 151976 Hom.: 49341 Cov.: 34

Gnomad AFR AF: 0.407

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.914

Gnomad EAS AF: 0.938

Gnomad SAS AF: 0.934

Gnomad FIN AF: 0.915

Gnomad MID AF: 0.861

Gnomad NFE AF: 0.919

Gnomad OTH AF: 0.810

GnomAD2 exomes AF: 0.882 AC: 217490 AN: 246526 AF XY: 0.892

Gnomad AFR exome AF: 0.396

Gnomad AMR exome AF: 0.865

Gnomad ASJ exome AF: 0.915

Gnomad EAS exome AF: 0.942

Gnomad FIN exome AF: 0.924

Gnomad NFE exome AF: 0.919

Gnomad OTH exome AF: 0.904

GnomAD4 exome AF: 0.907 AC: 1324103 AN: 1460454 Hom.: 605382 Cov.: 52 AF XY: 0.909 AC XY: 660477 AN XY: 726518

African (AFR) AF: 0.393 AC: 13140 AN: 33464

American (AMR) AF: 0.862 AC: 38485 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.918 AC: 23981 AN: 26132

East Asian (EAS) AF: 0.935 AC: 37110 AN: 39686

South Asian (SAS) AF: 0.930 AC: 80169 AN: 86242

European-Finnish (FIN) AF: 0.925 AC: 48490 AN: 52434

Middle Eastern (MID) AF: 0.897 AC: 5119 AN: 5706

European-Non Finnish (NFE) AF: 0.921 AC: 1023856 AN: 1111766

Other (OTH) AF: 0.891 AC: 53753 AN: 60356

GnomAD4 genome AF: 0.772 AC: 117463 AN: 152094 Hom.: 49337 Cov.: 34 AF XY: 0.779 AC XY: 57946 AN XY: 74360

African (AFR) AF: 0.407 AC: 16826 AN: 41370

American (AMR) AF: 0.859 AC: 13147 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.914 AC: 3173 AN: 3472

East Asian (EAS) AF: 0.938 AC: 4846 AN: 5166

South Asian (SAS) AF: 0.933 AC: 4504 AN: 4826

European-Finnish (FIN) AF: 0.915 AC: 9698 AN: 10594

Middle Eastern (MID) AF: 0.857 AC: 252 AN: 294

European-Non Finnish (NFE) AF: 0.918 AC: 62492 AN: 68038

Other (OTH) AF: 0.809 AC: 1708 AN: 2110

Alfa AF: 0.884 Hom.: 103083

Bravo AF: 0.752

Asia WGS AF: 0.880 AC: 3061 AN: 3478

EpiCase AF: 0.923

EpiControl AF: 0.923

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	15
DANN	Benign	0.75
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0074
dbscSNV1_RF	Benign	0.034
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: rs2576092; hg19: chr15-45408933;