12-21437687-T-C

Variant names:

• chr12-21437687-T-C
• rs2058464
• NM_024854.5:c.-44T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024854.5(PYROXD1):​c.-44T>C variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.49 in 1,573,474 control chromosomes in the GnomAD database, including 189,865 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18596 hom., cov: 32)
  • Exomes 𝑓: 0.49 (171269 hom.)
• Consequence: PYROXD1 NM_024854.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -3.51
• Publications: 12 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 12-21437687-T-C is Benign according to our data. Variant chr12-21437687-T-C is described in ClinVar as Benign. ClinVar VariationId is 1277227.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.539 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	NM_024854.5	MANE Select	c.-44T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	NP_079130.2	Q8WU10-1
	PYROXD1	NM_024854.5	MANE Select	c.-44T>C		5_prime_UTR	Exon 1 of 12	NP_079130.2	Q8WU10-1
	PYROXD1	NM_001350913.2		c.-747T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	NP_001337842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.-44T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000240651.9	Q8WU10-1
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.-44T>C		5_prime_UTR	Exon 1 of 12	ENSP00000240651.9	Q8WU10-1
	PYROXD1	ENST00000887643.1		c.-44T>C		5_prime_UTR_premature_start_codon_gain	Exon 1 of 12	ENSP00000557702.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75023 AN: 151870 Hom.: 18576 Cov.: 32

Gnomad AFR AF: 0.502

Gnomad AMI AF: 0.539

Gnomad AMR AF: 0.511

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.556

Gnomad SAS AF: 0.449

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.491

Gnomad OTH AF: 0.511

GnomAD2 exomes AF: 0.482 AC: 94534 AN: 196108 AF XY: 0.481

Gnomad AFR exome AF: 0.483

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.470

Gnomad EAS exome AF: 0.567

Gnomad FIN exome AF: 0.446

Gnomad NFE exome AF: 0.484

Gnomad OTH exome AF: 0.500

GnomAD4 exome AF: 0.490 AC: 696466 AN: 1421486 Hom.: 171269 Cov.: 28 AF XY: 0.488 AC XY: 344121 AN XY: 704548

African (AFR) AF: 0.501 AC: 16513 AN: 32978

American (AMR) AF: 0.481 AC: 18505 AN: 38464

Ashkenazi Jewish (ASJ) AF: 0.471 AC: 11985 AN: 25442

East Asian (EAS) AF: 0.560 AC: 21579 AN: 38560

South Asian (SAS) AF: 0.459 AC: 37418 AN: 81542

European-Finnish (FIN) AF: 0.446 AC: 22780 AN: 51030

Middle Eastern (MID) AF: 0.553 AC: 2931 AN: 5302

European-Non Finnish (NFE) AF: 0.491 AC: 535020 AN: 1089196

Other (OTH) AF: 0.504 AC: 29735 AN: 58972

GnomAD4 genome AF: 0.494 AC: 75089 AN: 151988 Hom.: 18596 Cov.: 32 AF XY: 0.492 AC XY: 36572 AN XY: 74292

African (AFR) AF: 0.502 AC: 20803 AN: 41424

American (AMR) AF: 0.511 AC: 7810 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1605 AN: 3470

East Asian (EAS) AF: 0.556 AC: 2850 AN: 5130

South Asian (SAS) AF: 0.449 AC: 2164 AN: 4824

European-Finnish (FIN) AF: 0.446 AC: 4709 AN: 10568

Middle Eastern (MID) AF: 0.588 AC: 173 AN: 294

European-Non Finnish (NFE) AF: 0.491 AC: 33395 AN: 67970

Other (OTH) AF: 0.515 AC: 1088 AN: 2112

Alfa AF: 0.472 Hom.: 7959

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

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Myofibrillar myopathy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.39
DANN	Benign	0.52
PhyloP100		-3.5
PromoterAI		-0.019	Neutral
Mutation Taster		=298/2	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2058464; hg19: chr12-21590621;