rs2110165

Positions:

• chr12-21437854-C-A
• chr12-21437854-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.302

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PYROXD1	NM_024854.5	c.84+40C>A		intron_variant		ENST00000240651.14	NP_079130.2
PYROXD1	NM_001350913.2	c.-620+40C>A		intron_variant			NP_001337842.1
PYROXD1	XM_006719153.4	c.84+40C>A		intron_variant			XP_006719216.1
PYROXD1	XM_047429554.1	c.84+40C>A		intron_variant			XP_047285510.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14	c.84+40C>A		intron_variant		1	NM_024854.5	ENSP00000240651	P1
PYROXD1	ENST00000544970.5	c.84+40C>A		intron_variant, NMD_transcript_variant		1		ENSP00000439106
PYROXD1	ENST00000375266.8	c.84+40C>A		intron_variant, NMD_transcript_variant		5		ENSP00000364415
PYROXD1	ENST00000543476.5	c.84+40C>A		intron_variant, NMD_transcript_variant		5		ENSP00000440192

Frequencies

GnomAD3 genomes AF: 0.493 AC: 75014 AN: 152040 Hom.: 18563 Cov.: 33

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

GnomAD3 exomes AF: 0.488 AC: 104479 AN: 214048 Hom.: 25398 AF XY: 0.487 AC XY: 56421 AN XY: 115776

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 SAS exome AF: 0.463

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.: 24 AF XY: 0.489 AC XY: 344841 AN XY: 704620

Gnomad4 AFR exome AF: 0.501

Gnomad4 AMR exome AF: 0.480

Gnomad4 ASJ exome AF: 0.470

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.459

Gnomad4 FIN exome AF: 0.446

Gnomad4 NFE exome AF: 0.493

Gnomad4 OTH exome AF: 0.505

GnomAD4 genome AF: 0.493 AC: 75080 AN: 152158 Hom.: 18583 Cov.: 33 AF XY: 0.492 AC XY: 36568 AN XY: 74392

Gnomad4 AFR AF: 0.501

Gnomad4 AMR AF: 0.510

Gnomad4 ASJ AF: 0.462

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.449

Gnomad4 FIN AF: 0.444

Gnomad4 NFE AF: 0.491

Gnomad4 OTH AF: 0.515

Alfa AF: 0.492 Hom.: 11313

Bravo AF: 0.500

Asia WGS AF: 0.555 AC: 1931 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	- -

Myofibrillar myopathy 8 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Nov 07, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	6.9
DANN	Benign	0.87

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

Other links and lift over

dbSNP: rs2110165; hg19: chr12-21590788;