rs1057518755

Variant names:

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

Variant summary

Our verdict is Pathogenic. Variant got 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

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 Pathogenic. Variant got 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 id is 372282.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PYROXD1	NM_024854.5	c.1160_1163dupCAAA	p.Lys388AsnfsTer14	frameshift_variant	Exon 11 of 12	ENST00000240651.14	NP_079130.2
PYROXD1	NM_001350912.2	c.947_950dupCAAA	p.Lys317AsnfsTer14	frameshift_variant	Exon 11 of 12		NP_001337841.1
PYROXD1	NM_001350913.2	c.383_386dupCAAA	p.Lys129AsnfsTer14	frameshift_variant	Exon 10 of 11		NP_001337842.1
PYROXD1	XM_017019976.3	c.416_419dupCAAA	p.Lys140AsnfsTer14	frameshift_variant	Exon 5 of 6		XP_016875465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PYROXD1	ENST00000240651.14	c.1160_1163dupCAAA	p.Lys388AsnfsTer14	frameshift_variant	Exon 11 of 12	1	NM_024854.5	ENSP00000240651.9

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Myofibrillar myopathy 8 Pathogenic:1

Dec 19, 2016

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1057518755; hg19: chr12-21620457;