12-21437623-A-C

Position:

• chr12-21437623-A-C

Variant summary

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

The ENST00000543476.5(PYROXD1):​c.-108A>C variant causes a 5 prime UTR, NMD transcript 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 5_prime_UTR, NMD_transcript
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.105

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=-0.77).
• BP6: Variant 12-21437623-A-C is Benign according to our data. Variant chr12-21437623-A-C is described in ClinVar as [Benign]. Clinvar id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYROXD1	NM_024854.5			upstream_gene_variant		ENST00000240651.14
PYROXD1	NM_001350913.2			upstream_gene_variant
PYROXD1	XM_006719153.4			upstream_gene_variant
PYROXD1	XM_047429554.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYROXD1	ENST00000543476.5	c.-108A>C		5_prime_UTR_variant, NMD_transcript_variant	1/9	5
PYROXD1	ENST00000240651.14			upstream_gene_variant		1	NM_024854.5	P1
PYROXD1	ENST00000375266.8			upstream_gene_variant		5

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

Gnomad4 AFR exome AF: 0.509

Gnomad4 AMR exome AF: 0.494

Gnomad4 ASJ exome AF: 0.490

Gnomad4 EAS exome AF: 0.560

Gnomad4 SAS exome AF: 0.471

Gnomad4 FIN exome AF: 0.499

Gnomad4 NFE exome AF: 0.543

Gnomad4 OTH exome AF: 0.543

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

Gnomad4 AFR AF: 0.509

Gnomad4 AMR AF: 0.530

Gnomad4 ASJ AF: 0.487

Gnomad4 EAS AF: 0.555

Gnomad4 SAS AF: 0.457

Gnomad4 FIN AF: 0.502

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.540

Alfa AF: 0.524 Hom.: 2810

Bravo AF: 0.525

Asia WGS AF: 0.559 AC: 1946 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	8.6
DANN	Benign	0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs2058463; hg19: chr12-21590557; COSMIC: COSV53710952;