Genetic Variant PYROXD2:p.Ala533Thr (chr10-98385025-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_032709.3(PYROXD2):c.1597G>A(p.Ala533Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 1,613,086 control chromosomes in the GnomAD database, including 89,731 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.34 ( 9303 hom., cov: 32)

Exomes 𝑓: 0.32 ( 80428 hom. )

Consequence

PYROXD2
NM_032709.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.990

Publications

41 publications found

Variant links:

Genes affected

PYROXD2 (HGNC:23517): (pyridine nucleotide-disulphide oxidoreductase domain 2) Predicted to enable oxidoreductase activity. Involved in mitochondrion organization. Located in mitochondrial matrix. [provided by Alliance of Genome Resources, Apr 2022]

PYROXD2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=7.484853E-4).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.522 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYROXD2	NM_032709.3 link	c.1597G>A	p.Ala533Thr	missense_variant	Exon 15 of 16	ENST00000370575.5	NP_116098.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYROXD2	ENST00000370575.5 link	c.1597G>A	p.Ala533Thr	missense_variant	Exon 15 of 16	1	NM_032709.3	ENSP00000359607.4
PYROXD2	ENST00000483923.5 link	n.2483G>A		non_coding_transcript_exon_variant	Exon 14 of 15	1

Frequencies

GnomAD3 genomes

AF:

0.343

AC:

52079

AN:

151760

Hom.:

9297

Cov.:

show subpopulations

Gnomad AFR

AF:

0.371

Gnomad AMI

AF:

0.388

Gnomad AMR

AF:

0.417

Gnomad ASJ

AF:

0.359

Gnomad EAS

AF:

0.425

Gnomad SAS

AF:

0.540

Gnomad FIN

AF:

0.291

Gnomad MID

AF:

0.269

Gnomad NFE

AF:

0.297

Gnomad OTH

AF:

0.312

GnomAD2 exomes

AF:

0.371

AC:

92941

AN:

250280

AF XY:

0.372

show subpopulations

Gnomad AFR exome

AF:

0.371

Gnomad AMR exome

AF:

0.499

Gnomad ASJ exome

AF:

0.357

Gnomad EAS exome

AF:

0.417

Gnomad FIN exome

AF:

0.287

Gnomad NFE exome

AF:

0.302

Gnomad OTH exome

AF:

0.343

GnomAD4 exome

AF:

0.323

AC:

472436

AN:

1461208

Hom.:

80428

Cov.:

AF XY:

0.328

AC XY:

238739

AN XY:

726862

show subpopulations

African (AFR)

AF:

0.371

AC:

12406

AN:

33460

American (AMR)

AF:

0.488

AC:

21782

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.357

AC:

9336

AN:

26128

East Asian (EAS)

AF:

0.418

AC:

16560

AN:

39662

South Asian (SAS)

AF:

0.528

AC:

45468

AN:

86168

European-Finnish (FIN)

AF:

0.286

AC:

15239

AN:

53278

Middle Eastern (MID)

AF:

0.343

AC:

1971

AN:

5744

European-Non Finnish (NFE)

AF:

0.296

AC:

329332

AN:

1111746

Other (OTH)

AF:

0.337

AC:

20342

AN:

60368

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

17496

34991

52487

69982

87478

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

11136

22272

33408

44544

55680

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.343

AC:

52108

AN:

151878

Hom.:

9303

Cov.:

AF XY:

0.349

AC XY:

25895

AN XY:

74240

show subpopulations

African (AFR)

AF:

0.371

AC:

15374

AN:

41422

American (AMR)

AF:

0.417

AC:

6366

AN:

15250

Ashkenazi Jewish (ASJ)

AF:

0.359

AC:

1247

AN:

3472

East Asian (EAS)

AF:

0.424

AC:

2185

AN:

5148

South Asian (SAS)

AF:

0.539

AC:

2588

AN:

4798

European-Finnish (FIN)

AF:

0.291

AC:

3078

AN:

10564

Middle Eastern (MID)

AF:

0.262

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.297

AC:

20187

AN:

67914

Other (OTH)

AF:

0.310

AC:

653

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

1677

3355

5032

6710

8387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

534

1068

1602

2136

2670

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.319

Hom.:

26916

Bravo

AF:

0.351

TwinsUK

AF:

0.294

AC:

1090

ALSPAC

AF:

0.307

AC:

1182

ESP6500AA

AF:

0.373

AC:

1642

ESP6500EA

AF:

0.303

AC:

2610

ExAC

AF:

0.369

AC:

44853

Asia WGS

AF:

0.463

AC:

1606

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.31

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.51

LIST_S2

Uncertain

0.96

MetaRNN

Benign

0.00075

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.94

PhyloP100

0.99

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.74

REVEL

Benign

0.056

Sift

Benign

0.64

Sift4G

Benign

0.57

Polyphen

0.12

Vest4

0.039

MPC

0.033

ClinPred

0.014

GERP RS

5.2

Varity_R

0.075

gMVP

0.44

Mutation Taster

=92/8

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over