12-21437623-A-C

Variant names:

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

Variant summary

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

The ENST00000543476.5(PYROXD1):​n.-108A>C variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.53 in 1,070,330 control chromosomes in the GnomAD database, including 151,111 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.52 (20742 hom., cov: 32)
  • Exomes 𝑓: 0.53 (130369 hom.)
• Consequence: PYROXD1 ENST00000543476.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-21437623-A-C is Benign according to our data. Variant chr12-21437623-A-C is described in ClinVar as Benign. ClinVar VariationId is 1228725.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: 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>C		upstream_gene	N/A	NP_079130.2	Q8WU10-1
	PYROXD1	NM_001350913.2		c.-811A>C		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>C		non_coding_transcript_exon	Exon 1 of 9	ENSP00000440192.1	B4DEW4
	PYROXD1	ENST00000543476.5	TSL:5	n.-108A>C		5_prime_UTR	Exon 1 of 9	ENSP00000440192.1	B4DEW4
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.-108A>C		upstream_gene	N/A	ENSP00000240651.9	Q8WU10-1

Frequencies

GnomAD3 genomes AF: 0.522 AC: 79271 AN: 151918 Hom.: 20722 Cov.: 32

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.579

Gnomad AMR AF: 0.529

Gnomad ASJ AF: 0.487

Gnomad EAS AF: 0.555

Gnomad SAS AF: 0.458

Gnomad FIN AF: 0.502

Gnomad MID AF: 0.582

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.535

GnomAD4 exome AF: 0.532 AC: 488416 AN: 918294 Hom.: 130369 Cov.: 12 AF XY: 0.529 AC XY: 249257 AN XY: 471618

African (AFR) AF: 0.509 AC: 11360 AN: 22310

American (AMR) AF: 0.494 AC: 16900 AN: 34192

Ashkenazi Jewish (ASJ) AF: 0.490 AC: 10626 AN: 21696

East Asian (EAS) AF: 0.560 AC: 18842 AN: 33660

South Asian (SAS) AF: 0.471 AC: 32464 AN: 68942

European-Finnish (FIN) AF: 0.499 AC: 24054 AN: 48242

Middle Eastern (MID) AF: 0.555 AC: 1771 AN: 3192

European-Non Finnish (NFE) AF: 0.543 AC: 349724 AN: 644298

Other (OTH) AF: 0.543 AC: 22675 AN: 41762

GnomAD4 genome AF: 0.522 AC: 79337 AN: 152036 Hom.: 20742 Cov.: 32 AF XY: 0.520 AC XY: 38669 AN XY: 74298

African (AFR) AF: 0.509 AC: 21106 AN: 41450

American (AMR) AF: 0.530 AC: 8091 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.487 AC: 1689 AN: 3466

East Asian (EAS) AF: 0.555 AC: 2853 AN: 5140

South Asian (SAS) AF: 0.457 AC: 2201 AN: 4812

European-Finnish (FIN) AF: 0.502 AC: 5312 AN: 10582

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36243 AN: 67988

Other (OTH) AF: 0.540 AC: 1140 AN: 2112

Alfa AF: 0.523 Hom.: 2910

Bravo AF: 0.525

Asia WGS AF: 0.559 AC: 1946 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.48
PhyloP100		0.10
PromoterAI		0.095	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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; COSMIC: COSV53710952;