rs4774518

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_207581.4(DUOXA2):c.738C>G(p.Tyr246*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000411 in 1,603,982 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. Y246Y) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

DUOXA2
NM_207581.4 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4

Conservation

PhyloP100: -1.77

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:

DUOXA2 (HGNC:):

DUOXA2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.234 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 15-45117274-C-G is Pathogenic according to our data. Variant chr15-45117274-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 444.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DUOXA2	NM_207581.4 linkuse as main transcript	c.738C>G	p.Tyr246*	stop_gained	5/6	ENST00000323030.6	NP_997464.2	Q1HG44-1
DUOXA2	XM_017022180.2 linkuse as main transcript	c.789C>G	p.Tyr263*	stop_gained	5/6		XP_016877669.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
DUOXA2	ENST00000323030.6 linkuse as main transcript	c.738C>G	p.Tyr246*	stop_gained	5/6	1	NM_207581.4	ENSP00000319705.5	Q1HG44-1
DUOXA2	ENST00000491993.2 linkuse as main transcript	n.*805C>G		non_coding_transcript_exon_variant	5/6	1		ENSP00000454110.1	Q1HG44-2
DUOXA2	ENST00000491993.2 linkuse as main transcript	n.*805C>G		3_prime_UTR_variant	5/6	1		ENSP00000454110.1	Q1HG44-2
DUOXA2	ENST00000350243.10 linkuse as main transcript	n.1379C>G		non_coding_transcript_exon_variant	4/5	2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00154

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000143

AC:

AN:

237622

Hom.:

AF XY:

0.000162

AC XY:

AN XY:

129994

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00186

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000931

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000386

AC:

AN:

1451624

Hom.:

Cov.:

AF XY:

0.0000388

AC XY:

AN XY:

720768

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00114

Gnomad4 SAS exome

AF:

0.0000585

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000181

Gnomad4 OTH exome

AF:

0.0000668

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152358

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74498

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00174

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Bravo

AF:

0.0000831

ExAC

AF:

0.000157

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Thyroglobulin synthesis defect

Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Juno Genomics, Hangzhou Juno Genomics, Inc	-	PVS1_Strong+PM3_VeryStrong+PP4+PP1 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 01, 2008	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 27, 2022	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 31, 2021

The c.738C>G (p.Y246*) alteration, located in exon 5 (coding exon 5) of the DUOXA2 gene, consists of a C to G substitution at nucleotide position 738. This changes the amino acid from a tyrosine (Y) to a stop codon at amino acid position 246. This alteration occurs at the 3' terminus of the DUOXA2 gene, is not expected to trigger nonsense-mediated mRNA decay, and only impacts the last 23.4% (75/320 amino acids) of the protein. However, premature stop codons are typically deleterious in nature and a significant portion of the protein is affected (Ambry internal data). This alteration has been reported in the homozygous state and in trans with a second DUOXA2 mutation in several patients with congenital hypothyroidism (Zamproni, 2008; Yi, 2013; Liu, 2015; Tanase-Nakao, 2018; Jung, 2020). In vitro studies showed reduced protein expression and inability to reconstitute DUOX2 activity, consistent with complete loss of function (Zamproni, 2008). Based on the available evidence, this alteration is classified as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.42

CADD

Benign

DANN

Uncertain

0.98

Eigen

Benign

-0.59

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.46

Vest4

0.81

GERP RS

-2.3

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

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