rs369083786

Variant names:

• chr12-21445467-G-A
• rs369083786
• NM_024854.5:c.285+1G>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_024854.5(PYROXD1):​c.285+1G>A variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,581,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: PYROXD1 NM_024854.5 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 8.45
• Publications: 3 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07984032 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PP5: Variant 12-21445467-G-A is Pathogenic according to our data. Variant chr12-21445467-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 372278.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYROXD1	NM_024854.5	c.285+1G>A		splice_donor_variant, intron_variant	Intron 3 of 11	ENST00000240651.14	NP_079130.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14	c.285+1G>A		splice_donor_variant, intron_variant	Intron 3 of 11	1	NM_024854.5	ENSP00000240651.9

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000864 AC: 19 AN: 219878 AF XY: 0.0000837

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000162

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000143

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000204 AC: 292 AN: 1429578 Hom.: 0 Cov.: 31 AF XY: 0.000193 AC XY: 137 AN XY: 710694

African (AFR) AF: 0.0000634 AC: 2 AN: 31540

American (AMR) AF: 0.000145 AC: 5 AN: 34486

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24268

East Asian (EAS) AF: 0.00 AC: 0 AN: 39364

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79656

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52748

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5602

European-Non Finnish (NFE) AF: 0.000250 AC: 276 AN: 1102908

Other (OTH) AF: 0.000119 AC: 7 AN: 59006

GnomAD4 genome AF: 0.0000986 AC: 15 AN: 152152 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74334

African (AFR) AF: 0.0000483 AC: 2 AN: 41428

American (AMR) AF: 0.000131 AC: 2 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000162 AC: 11 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.178 Hom.: 6553

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Myofibrillar myopathy 8 Pathogenic:3

Dec 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Jan 23, 2019

Baylor Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

May 02, 2023

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: curation

The heterozygous c.285+1G>A variant in PYROXD1 was identified by our study, in the compound heterozygous state with a variant of uncertain significance (NC_000012.12:g.21461062T>G), in one individual with limb girdle myopathy. Trio exome analysis revealed that this variant was in trans with a variant of uncertain significance (NC_000012.12:g.21461062T>G). The c.285+1G>A variant in PYROXD1 has been reported in six individuals with myofibrillar myopathy 8 (PMID: 27745833, PMID: 33333461, PMID: 32528171), but has been identified in 0.02% (4/25598) of Latino/Admixed American chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP ID: rs369083786). Although this variant has been seen in the general population in a heterozygous state, its frequency is not high enough to rule out a pathogenic role. This variant has also been reported in ClinVar (Variation ID: 372278) and has been interpreted as pathogenic by Invitae, Baylor Genetics, and OMIM, and as likely pathogenic by GeneDx. Of these six previously reported individuals, four were homozygotes (PMID: 32528171) and 1 was a compound heterozygote who carried a variant of uncertain significance in trans (PMID: 27745833, ClinVar ID: 372279), and, in addition, the patient identified by our study was a compound heterozygote who carried a variant of uncertain significance (NC_000012.12:g.21461062T>G) in trans, which increases the likelihood that the c.285+1G>A variant is pathogenic. RT-PCR analysis performed on affected muscle tissue showed evidence of exon skipping of exon 3 (PMID: 27745833). Exon 3 (NM_024854.5) is in-frame with 120 nucleotides (40 codons). This variant is located in the 5' splice region. Computational tools predict a splicing impact, though this information is not predictive enough to determine pathogenicity. Loss of function of the PYROXD1 gene is an established disease mechanism in autosomal recessive myofibrillar myopathy 8. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive myofibrillar myopathy 8. ACMG/AMP Criteria applied: PVS1_Moderate, PM3_Strong, PS3_Moderate (Richards 2015). -

not provided Pathogenic:2

Dec 06, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in an in-frame loss of the adjacent exon in a gene for which loss of function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 27745833, 31455395, 32528171, 33333461, 34694888) -

Dec 18, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 3 of the PYROXD1 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and likely results in a shortened protein product. This variant is present in population databases (rs369083786, gnomAD 0.02%). Disruption of this splice site has been observed in individual(s) with early-onset myopathy (PMID: 27745833, 31455395). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 372278). Studies have shown that disruption of this splice site results in skipping of exon 3, but is expected to preserve the integrity of the reading-frame (PMID: 27745833). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.5
GERP RS		5.3
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.99		Position offset: -1

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

Other links and lift over

dbSNP: rs369083786; hg19: chr12-21598401;