rs1057518755

Variant names:

• chr12-21467523-G-GCAAA
• rs1057518755
• NM_024854.5:c.1160_1163dupCAAA

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024854.5(PYROXD1):​c.1160_1163dupCAAA​(p.Lys388AsnfsTer14) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PYROXD1 NM_024854.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 3.81
• Publications: 2 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 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 12-21467523-G-GCAAA is Pathogenic according to our data. Variant chr12-21467523-G-GCAAA is described in ClinVar as Pathogenic. ClinVar VariationId is 372282.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024854.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	NM_024854.5	MANE Select	c.1160_1163dupCAAA	p.Lys388AsnfsTer14	frameshift	Exon 11 of 12	NP_079130.2
	PYROXD1	NM_001350912.2		c.947_950dupCAAA	p.Lys317AsnfsTer14	frameshift	Exon 11 of 12	NP_001337841.1
	PYROXD1	NM_001350913.2		c.383_386dupCAAA	p.Lys129AsnfsTer14	frameshift	Exon 10 of 11	NP_001337842.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.1160_1163dupCAAA	p.Lys388AsnfsTer14	frameshift	Exon 11 of 12	ENSP00000240651.9
	PYROXD1	ENST00000544970.5	TSL:1	n.*666_*669dupCAAA		non_coding_transcript_exon	Exon 10 of 11	ENSP00000439106.1
	PYROXD1	ENST00000544970.5	TSL:1	n.*666_*669dupCAAA		3_prime_UTR	Exon 10 of 11	ENSP00000439106.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Myofibrillar myopathy 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.8
Mutation Taster		=7/193	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs1057518755; hg19: chr12-21620457;