Genetic Variant DUOXA2:c.554+6T>C (chr15-45116735-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 ClinVar 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 Lovd as [Benign].

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 link	c.554+6T>C		splice_region_variant, intron_variant	Intron 4 of 5	ENST00000323030.6	NP_997464.2	Q1HG44-1
DUOXA2	XM_017022180.2 link	c.605+6T>C		splice_region_variant, intron_variant	Intron 4 of 5		XP_016877669.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
DUOXA2	ENST00000323030.6 link	c.554+6T>C	splice_region_variant, intron_variant	Intron 4 of 5	1	NM_207581.4	ENSP00000319705.5	Q1HG44-1
DUOXA2	ENST00000491993.2 link	n.*621+6T>C	splice_region_variant, intron_variant	Intron 4 of 5	1		ENSP00000454110.1	Q1HG44-2
DUOXA2	ENST00000350243.10 link	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.:

show subpopulations

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

GnomAD3 exomes

AF:

0.882

AC:

217490

AN:

246526

Hom.:

98050

AF XY:

0.892

AC XY:

119743

AN XY:

134270

show subpopulations

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 SAS exome

AF:

0.929

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.:

AF XY:

0.909

AC XY:

660477

AN XY:

726518

show subpopulations

Gnomad4 AFR exome

AF:

0.393

Gnomad4 AMR exome

AF:

0.862

Gnomad4 ASJ exome

AF:

0.918

Gnomad4 EAS exome

AF:

0.935

Gnomad4 SAS exome

AF:

0.930

Gnomad4 FIN exome

AF:

0.925

Gnomad4 NFE exome

AF:

0.921

Gnomad4 OTH exome

AF:

0.891

GnomAD4 genome

AF:

0.772

AC:

117463

AN:

152094

Hom.:

49337

Cov.:

AF XY:

0.779

AC XY:

57946

AN XY:

74360

show subpopulations

Gnomad4 AFR

AF:

0.407

Gnomad4 AMR

AF:

0.859

Gnomad4 ASJ

AF:

0.914

Gnomad4 EAS

AF:

0.938

Gnomad4 SAS

AF:

0.933

Gnomad4 FIN

AF:

0.915

Gnomad4 NFE

AF:

0.918

Gnomad4 OTH

AF:

0.809

Alfa

AF:

0.900

Hom.:

75092

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

LINK: link

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

- -

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

DANN

Benign

0.75

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over