Genetic Variant NM_024854.5:c.84+40C>A (chr12-21437854-C-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_024854.5(PYROXD1):c.84+40C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.491 in 1,570,224 control chromosomes in the GnomAD database, including 189,640 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.49 ( 18583 hom., cov: 33)

Exomes 𝑓: 0.49 ( 171057 hom. )

Consequence

PYROXD1
NM_024854.5 intron

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.302

Publications

12 publications found

Variant links:

Genes affected

PYROXD1 (HGNC:26162): (pyridine nucleotide-disulphide oxidoreductase domain 1) This gene encodes a nuclear-cytoplasmic pyridine nucleotide-disulphide reductase (PNDR). PNDRs are flavoproteins that catalyze the pyridine nucleotide-dependent reduction of thiol residues in other proteins. The encoded protein belongs to the class I pyridine nucleotide-disulphide oxidoreductase family but lacks the C-terminal dimerization domain found in other family members and instead has a C-terminal nitrile reductase domain. It localizes to the nucleus and to striated sarcomeric compartments. Naturally occurring mutations in this gene cause early-onset myopathy with internalized nuclei and myofibrillar disorganization. A pseudogene of this gene has been defined on chromosome 11. [provided by RefSeq, Apr 2017]

PYROXD1 Gene-Disease associations (from GenCC):

myofibrillar myopathy 8
Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

PYROXD1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.63).

BP6

Variant 12-21437854-C-A is Benign according to our data. Variant chr12-21437854-C-A is described in ClinVar as Benign. ClinVar VariationId is 1253388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.538 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024854.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PYROXD1	NM_024854.5	MANE Select	c.84+40C>A	intron	N/A	NP_079130.2	Q8WU10-1
PYROXD1	NM_001350913.2		c.-620+40C>A	intron	N/A	NP_001337842.1
PYROXD1	NM_001350912.2		c.-814C>A	upstream_gene	N/A	NP_001337841.1	Q8WU10-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.84+40C>A	intron	N/A	ENSP00000240651.9	Q8WU10-1
PYROXD1	ENST00000544970.5	TSL:1	n.84+40C>A	intron	N/A	ENSP00000439106.1	B4DEW4
PYROXD1	ENST00000887643.1		c.84+40C>A	intron	N/A	ENSP00000557702.1

Frequencies

GnomAD3 genomes

AF:

0.493

AC:

75014

AN:

152040

Hom.:

18563

Cov.:

show subpopulations

Gnomad AFR

AF:

0.502

Gnomad AMI

AF:

0.539

Gnomad AMR

AF:

0.510

Gnomad ASJ

AF:

0.462

Gnomad EAS

AF:

0.555

Gnomad SAS

AF:

0.449

Gnomad FIN

AF:

0.444

Gnomad MID

AF:

0.579

Gnomad NFE

AF:

0.491

Gnomad OTH

AF:

0.510

GnomAD2 exomes

AF:

0.488

AC:

104479

AN:

214048

AF XY:

0.487

show subpopulations

Gnomad AFR exome

AF:

0.496

Gnomad AMR exome

AF:

0.477

Gnomad ASJ exome

AF:

0.470

Gnomad EAS exome

AF:

0.572

Gnomad FIN exome

AF:

0.448

Gnomad NFE exome

AF:

0.492

Gnomad OTH exome

AF:

0.500

GnomAD4 exome

AF:

0.491

AC:

696339

AN:

1418066

Hom.:

171057

Cov.:

AF XY:

0.489

AC XY:

344841

AN XY:

704620

show subpopulations

African (AFR)

AF:

0.501

AC:

16444

AN:

32792

American (AMR)

AF:

0.480

AC:

19746

AN:

41114

Ashkenazi Jewish (ASJ)

AF:

0.470

AC:

11861

AN:

25236

East Asian (EAS)

AF:

0.560

AC:

21732

AN:

38822

South Asian (SAS)

AF:

0.459

AC:

37943

AN:

82674

European-Finnish (FIN)

AF:

0.446

AC:

22863

AN:

51272

Middle Eastern (MID)

AF:

0.556

AC:

3152

AN:

5672

European-Non Finnish (NFE)

AF:

0.493

AC:

532890

AN:

1081658

Other (OTH)

AF:

0.505

AC:

29708

AN:

58826

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

16769

33538

50308

67077

83846

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15654

31308

46962

62616

78270

<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:

0.493

AC:

75080

AN:

152158

Hom.:

18583

Cov.:

AF XY:

0.492

AC XY:

36568

AN XY:

74392

show subpopulations

African (AFR)

AF:

0.501

AC:

20813

AN:

41516

American (AMR)

AF:

0.510

AC:

7803

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.462

AC:

1604

AN:

3470

East Asian (EAS)

AF:

0.555

AC:

2869

AN:

5172

South Asian (SAS)

AF:

0.449

AC:

2167

AN:

4830

European-Finnish (FIN)

AF:

0.444

AC:

4707

AN:

10592

Middle Eastern (MID)

AF:

0.588

AC:

173

AN:

294

European-Non Finnish (NFE)

AF:

0.491

AC:

33365

AN:

67958

Other (OTH)

AF:

0.515

AC:

1087

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2014

4029

6043

8058

10072

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

682

1364

2046

2728

3410

<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:

0.492

Hom.:

12911

Bravo

AF:

0.500

Asia WGS

AF:

0.555

AC:

1931

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Myofibrillar myopathy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.63

CADD

Benign

6.9

(source)

DANN

Benign

0.87

PhyloP100

0.30

PromoterAI

-0.036

Neutral

(source)

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over