12-21440073-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_024854.5(PYROXD1):c.85-295G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0321 in 152,142 control chromosomes in the GnomAD database, including 114 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.032 (114 hom., cov: 32)
• Consequence: PYROXD1 NM_024854.5 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.628

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 12-21440073-G-C is Benign according to our data. Variant chr12-21440073-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 1203918.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0321 (4890/152142) while in subpopulation NFE AF= 0.0481 (3273/67996). AF 95% confidence interval is 0.0468. There are 114 homozygotes in gnomad4. There are 2284 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 114 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYROXD1	NM_024854.5	c.85-295G>C		intron_variant		ENST00000240651.14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYROXD1	ENST00000240651.14	c.85-295G>C		intron_variant		1	NM_024854.5	P1

Frequencies

GnomAD3 genomes AF: 0.0322 AC: 4896 AN: 152024 Hom.: 114 Cov.: 32

Gnomad AFR AF: 0.00841

Gnomad AMI AF: 0.0471

Gnomad AMR AF: 0.0394

Gnomad ASJ AF: 0.0585

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.0315

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0481

Gnomad OTH AF: 0.0506

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0321 AC: 4890 AN: 152142 Hom.: 114 Cov.: 32 AF XY: 0.0307 AC XY: 2284 AN XY: 74384

Gnomad4 AFR AF: 0.00839

Gnomad4 AMR AF: 0.0393

Gnomad4 ASJ AF: 0.0585

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0310

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.0481

Gnomad4 OTH AF: 0.0510

Alfa AF: 0.0129 Hom.: 2

Bravo AF: 0.0330

Asia WGS AF: 0.0130 AC: 44 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely 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	-0.87
Cadd	Benign	0.47
Dann	Benign	0.78

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: rs17620142; hg19: chr12-21593007;