12-21437666-C-T

Position:

• chr12-21437666-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024854.5(PYROXD1):​c.-65C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0182 in 1,516,820 control chromosomes in the GnomAD database, including 322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (37 hom., cov: 33)
  • Exomes 𝑓: 0.018 (285 hom.)
• Consequence: PYROXD1 NM_024854.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.633

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 12-21437666-C-T is Benign according to our data. Variant chr12-21437666-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1199668.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.02 (3049/152188) while in subpopulation AFR AF= 0.0246 (1021/41480). AF 95% confidence interval is 0.0234. There are 37 homozygotes in gnomad4. There are 1491 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PYROXD1	NM_024854.5	c.-65C>T		5_prime_UTR_variant	1/12	ENST00000240651.14
PYROXD1	NM_001350913.2	c.-768C>T		5_prime_UTR_variant	1/11
PYROXD1	XM_006719153.4	c.-65C>T		5_prime_UTR_variant	1/8
PYROXD1	XM_047429554.1	c.-65C>T		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PYROXD1	ENST00000240651.14	c.-65C>T		5_prime_UTR_variant	1/12	1	NM_024854.5	P1
PYROXD1	ENST00000375266.8	c.-65C>T		5_prime_UTR_variant, NMD_transcript_variant	1/13	5
PYROXD1	ENST00000543476.5	c.-65C>T		5_prime_UTR_variant, NMD_transcript_variant	1/9	5
PYROXD1	ENST00000544970.5			upstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3032 AN: 152068 Hom.: 35 Cov.: 33

Gnomad AFR AF: 0.0243

Gnomad AMI AF: 0.0297

Gnomad AMR AF: 0.0141

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0114

Gnomad FIN AF: 0.0202

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0208

Gnomad OTH AF: 0.0225

GnomAD4 exome AF: 0.0180 AC: 24611 AN: 1364632 Hom.: 285 Cov.: 23 AF XY: 0.0179 AC XY: 12121 AN XY: 677442

Gnomad4 AFR exome AF: 0.0242

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0133

Gnomad4 EAS exome AF: 0.0000798

Gnomad4 SAS exome AF: 0.00910

Gnomad4 FIN exome AF: 0.0174

Gnomad4 NFE exome AF: 0.0193

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0200 AC: 3049 AN: 152188 Hom.: 37 Cov.: 33 AF XY: 0.0200 AC XY: 1491 AN XY: 74410

Gnomad4 AFR AF: 0.0246

Gnomad4 AMR AF: 0.0141

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0112

Gnomad4 FIN AF: 0.0202

Gnomad4 NFE AF: 0.0208

Gnomad4 OTH AF: 0.0223

Alfa AF: 0.0195 Hom.: 5

Bravo AF: 0.0203

Asia WGS AF: 0.00751 AC: 27 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	3.6
DANN	Benign	0.90

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs113744302; hg19: chr12-21590600;