NM_207581.4:c.148-30C>T

Variant names:

• chr15-45115769-C-T
• rs28559568
• NM_207581.4:c.148-30C>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.148-30C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,992 control chromosomes in the GnomAD database, including 492 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.032 (133 hom., cov: 32)
  • Exomes 𝑓: 0.015 (359 hom.)
• Consequence: DUOXA2 NM_207581.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.325
• Publications: 2 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial thyroid dyshormonogenesis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 0 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 15-45115769-C-T is Benign according to our data. Variant chr15-45115769-C-T is described in ClinVar as Benign. ClinVar VariationId is 1270124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0674 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	NM_207581.4	MANE Select	c.148-30C>T		intron	N/A	NP_997464.2	Q1HG44-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DUOXA2	ENST00000323030.6	TSL:1 MANE Select	c.148-30C>T		intron	N/A	ENSP00000319705.5	Q1HG44-1
	DUOXA2	ENST00000491993.2	TSL:1	n.*185C>T		non_coding_transcript_exon	Exon 2 of 6	ENSP00000454110.1	Q1HG44-2
	DUOXA2	ENST00000491993.2	TSL:1	n.*185C>T		3_prime_UTR	Exon 2 of 6	ENSP00000454110.1	Q1HG44-2

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 4801 AN: 152082 Hom.: 132 Cov.: 32

Gnomad AFR AF: 0.0694

Gnomad AMI AF: 0.0582

Gnomad AMR AF: 0.0326

Gnomad ASJ AF: 0.0109

Gnomad EAS AF: 0.0663

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0136

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.0302

GnomAD2 exomes AF: 0.0245 AC: 6127 AN: 249842 AF XY: 0.0224

Gnomad AFR exome AF: 0.0725

Gnomad AMR exome AF: 0.0451

Gnomad ASJ exome AF: 0.00796

Gnomad EAS exome AF: 0.0690

Gnomad FIN exome AF: 0.0103

Gnomad NFE exome AF: 0.0111

Gnomad OTH exome AF: 0.0206

GnomAD4 exome AF: 0.0147 AC: 21523 AN: 1461792 Hom.: 359 Cov.: 32 AF XY: 0.0144 AC XY: 10499 AN XY: 727206

African (AFR) AF: 0.0719 AC: 2407 AN: 33480

American (AMR) AF: 0.0425 AC: 1899 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00826 AC: 216 AN: 26136

East Asian (EAS) AF: 0.0677 AC: 2688 AN: 39698

South Asian (SAS) AF: 0.0154 AC: 1326 AN: 86254

European-Finnish (FIN) AF: 0.0108 AC: 579 AN: 53398

Middle Eastern (MID) AF: 0.0111 AC: 64 AN: 5768

European-Non Finnish (NFE) AF: 0.0101 AC: 11178 AN: 1111966

Other (OTH) AF: 0.0193 AC: 1166 AN: 60392

GnomAD4 genome AF: 0.0317 AC: 4818 AN: 152200 Hom.: 133 Cov.: 32 AF XY: 0.0318 AC XY: 2370 AN XY: 74412

African (AFR) AF: 0.0695 AC: 2885 AN: 41516

American (AMR) AF: 0.0326 AC: 499 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0109 AC: 38 AN: 3472

East Asian (EAS) AF: 0.0658 AC: 341 AN: 5180

South Asian (SAS) AF: 0.0148 AC: 71 AN: 4812

European-Finnish (FIN) AF: 0.0136 AC: 144 AN: 10612

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0106 AC: 722 AN: 68004

Other (OTH) AF: 0.0309 AC: 65 AN: 2106

Alfa AF: 0.0167 Hom.: 81

Bravo AF: 0.0360

Asia WGS AF: 0.0800 AC: 278 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	15
DANN	Benign	0.80
PhyloP100		0.33
BranchPoint Hunter		0.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs28559568; hg19: chr15-45407967;