12-21437623-A-G

Variant names:

• chr12-21437623-A-G
• rs2058463
• ENST00000543476.5:n.-108A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000543476.5(PYROXD1):​n.-108A>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PYROXD1 ENST00000543476.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.105
• Publications: 9 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000543476.5. 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.-108A>G		upstream_gene	N/A	NP_079130.2	Q8WU10-1
	PYROXD1	NM_001350913.2		c.-811A>G		upstream_gene	N/A	NP_001337842.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	ENST00000543476.5	TSL:5	n.-108A>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 9	ENSP00000440192.1	B4DEW4
	PYROXD1	ENST00000543476.5	TSL:5	n.-108A>G		non_coding_transcript_exon	Exon 1 of 9	ENSP00000440192.1	B4DEW4
	PYROXD1	ENST00000543476.5	TSL:5	n.-108A>G		5_prime_UTR	Exon 1 of 9	ENSP00000440192.1	B4DEW4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000217 AC: 2 AN: 921834 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 473600

African (AFR) AF: 0.00 AC: 0 AN: 22424

American (AMR) AF: 0.00 AC: 0 AN: 34400

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21790

East Asian (EAS) AF: 0.00 AC: 0 AN: 33730

South Asian (SAS) AF: 0.00 AC: 0 AN: 69146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3204

European-Non Finnish (NFE) AF: 0.00000309 AC: 2 AN: 646872

Other (OTH) AF: 0.00 AC: 0 AN: 41916

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.6
DANN	Benign	0.65
PhyloP100		0.10
PromoterAI		0.16	Neutral

Splicing

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

Other links and lift over

dbSNP: rs2058463; hg19: chr12-21590557;