chr12-21437676-CCA-C

Variant names:

• chr12-21437676-CCA-C
• rs138292380
• NM_024854.5:c.-54_-53delCA

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_024854.5(PYROXD1):​c.-54_-53delCA variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0022 in 1,550,036 control chromosomes in the GnomAD database, including 36 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (19 hom.)
• Consequence: PYROXD1 NM_024854.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.38
• Publications: 1 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: Ambry Genetics, G2P, ClinGen, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 12-21437676-CCA-C is Benign according to our data. Variant chr12-21437676-CCA-C is described in ClinVar as Likely_benign. ClinVar VariationId is 1301018.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00791 (1205/152258) while in subpopulation AFR AF = 0.0239 (992/41540). AF 95% confidence interval is 0.0226. There are 17 homozygotes in GnomAd4. There are 595 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	NM_024854.5	MANE Select	c.-54_-53delCA		5_prime_UTR	Exon 1 of 12	NP_079130.2	Q8WU10-1
	PYROXD1	NM_001350913.2		c.-757_-756delCA		5_prime_UTR	Exon 1 of 11	NP_001337842.1
	PYROXD1	NM_001350912.2		c.-991_-990delCA		upstream_gene	N/A	NP_001337841.1	Q8WU10-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PYROXD1	ENST00000240651.14	TSL:1 MANE Select	c.-54_-53delCA		5_prime_UTR	Exon 1 of 12	ENSP00000240651.9	Q8WU10-1
	PYROXD1	ENST00000887643.1		c.-54_-53delCA		5_prime_UTR	Exon 1 of 12	ENSP00000557702.1
	PYROXD1	ENST00000964889.1		c.-54_-53delCA		5_prime_UTR	Exon 1 of 12	ENSP00000634948.1

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1203 AN: 152140 Hom.: 18 Cov.: 32

Gnomad AFR AF: 0.0239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000250

Gnomad OTH AF: 0.00765

GnomAD4 exome AF: 0.00158 AC: 2206 AN: 1397778 Hom.: 19 AF XY: 0.00146 AC XY: 1015 AN XY: 692898

African (AFR) AF: 0.0223 AC: 726 AN: 32514

American (AMR) AF: 0.00287 AC: 107 AN: 37294

Ashkenazi Jewish (ASJ) AF: 0.0328 AC: 827 AN: 25220

East Asian (EAS) AF: 0.00 AC: 0 AN: 38084

South Asian (SAS) AF: 0.000149 AC: 12 AN: 80544

European-Finnish (FIN) AF: 0.000178 AC: 9 AN: 50534

Middle Eastern (MID) AF: 0.00502 AC: 25 AN: 4982

European-Non Finnish (NFE) AF: 0.000234 AC: 250 AN: 1070446

Other (OTH) AF: 0.00430 AC: 250 AN: 58160

GnomAD4 genome AF: 0.00791 AC: 1205 AN: 152258 Hom.: 17 Cov.: 32 AF XY: 0.00799 AC XY: 595 AN XY: 74450

African (AFR) AF: 0.0239 AC: 992 AN: 41540

American (AMR) AF: 0.00360 AC: 55 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0349 AC: 121 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68026

Other (OTH) AF: 0.00757 AC: 16 AN: 2114

Alfa AF: 0.00705 Hom.: 1

Bravo AF: 0.00913

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.4
Mutation Taster		=300/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs138292380; hg19: chr12-21590610;