Genetic Variant PYROXD1:c.-54_-53delCA (chr12-21437676-CCA-C) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_024854.5(PYROXD1):c.-54_-53delCA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,550,036 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0079 ( 17 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 19 hom. )

Consequence

PYROXD1
NM_024854.5 5_prime_UTR

Scores

Not classified

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.38

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 12-21437676-CCA-C is Benign according to our data. Variant chr12-21437676-CCA-C is described in ClinVar as [Likely_benign]. Clinvar id is 1301018.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00791 (1205/152258) while in subpopulation AFR AF = 0.0239 (992/41540). AF 95% confidence interval is 0.0226. There are 17 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 17 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYROXD1	NM_024854.5 link	c.-54_-53delCA		5_prime_UTR_variant	Exon 1 of 12	ENST00000240651.14	NP_079130.2	Q8WU10-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14 link	c.-54_-53delCA		5_prime_UTR_variant	Exon 1 of 12	1	NM_024854.5	ENSP00000240651.9		Q8WU10-1

Frequencies

GnomAD3 genomes

AF:

0.00791

AC:

1203

AN:

152140

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00360

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000622

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00765

GnomAD4 exome

AF:

0.00158

AC:

2206

AN:

1397778

Hom.:

AF XY:

0.00146

AC XY:

1015

AN XY:

692898

show subpopulations

African (AFR)

AF:

0.0223

AC:

726

AN:

32514

American (AMR)

AF:

0.00287

AC:

107

AN:

37294

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

827

AN:

25220

East Asian (EAS)

AF:

0.00

AC:

AN:

38084

South Asian (SAS)

AF:

0.000149

AC:

AN:

80544

European-Finnish (FIN)

AF:

0.000178

AC:

AN:

50534

Middle Eastern (MID)

AF:

0.00502

AC:

AN:

4982

European-Non Finnish (NFE)

AF:

0.000234

AC:

250

AN:

1070446

Other (OTH)

AF:

0.00430

AC:

250

AN:

58160

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

114

228

343

457

571

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00791

AC:

1205

AN:

152258

Hom.:

Cov.:

AF XY:

0.00799

AC XY:

595

AN XY:

74450

show subpopulations

African (AFR)

AF:

0.0239

AC:

992

AN:

41540

American (AMR)

AF:

0.00360

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5166

South Asian (SAS)

AF:

0.000622

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000250

AC:

AN:

68026

Other (OTH)

AF:

0.00757

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

117

175

234

292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00705

Hom.:

Bravo

AF:

0.00913

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Jul 09, 2018

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

-2.4

Mutation Taster

=300/0

polymorphism

(source)

Splicing

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

Publications

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12-21437676-CCA-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over