12-21437770-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001350913.2(PYROXD1):​c.-664G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

PYROXD1
NM_001350913.2 5_prime_UTR_premature_start_codon_gain

Scores

1
1
17

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.76
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.127774).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
PYROXD1NM_024854.5 linkuse as main transcriptc.40G>T p.Val14Leu missense_variant 1/12 ENST00000240651.14 NP_079130.2 Q8WU10-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
PYROXD1ENST00000240651.14 linkuse as main transcriptc.40G>T p.Val14Leu missense_variant 1/121 NM_024854.5 ENSP00000240651.9 Q8WU10-1
PYROXD1ENST00000544970.5 linkuse as main transcriptn.40G>T non_coding_transcript_exon_variant 1/111 ENSP00000439106.1 B4DEW4
PYROXD1ENST00000375266.8 linkuse as main transcriptn.40G>T non_coding_transcript_exon_variant 1/135 ENSP00000364415.4 B5MDP1
PYROXD1ENST00000543476.5 linkuse as main transcriptn.40G>T non_coding_transcript_exon_variant 1/95 ENSP00000440192.1 B4DEW4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1460924
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726678
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpNov 09, 2021This variant has not been reported in the literature in individuals affected with PYROXD1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 14 of the PYROXD1 protein (p.Val14Leu). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.24
BayesDel_addAF
Uncertain
0.013
T
BayesDel_noAF
Benign
-0.22
CADD
Benign
21
DANN
Benign
0.92
DEOGEN2
Benign
0.067
T
Eigen
Benign
-0.24
Eigen_PC
Benign
-0.071
FATHMM_MKL
Benign
0.74
D
LIST_S2
Benign
0.78
T
M_CAP
Benign
0.018
T
MetaRNN
Benign
0.13
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
1.3
L
PrimateAI
Pathogenic
0.82
D
PROVEAN
Benign
-0.56
N
REVEL
Benign
0.093
Sift
Benign
0.59
T
Sift4G
Benign
0.55
T
Polyphen
0.013
B
Vest4
0.44
MutPred
0.56
Gain of catalytic residue at G19 (P = 0);
MVP
0.25
MPC
0.20
ClinPred
0.48
T
GERP RS
3.6
Varity_R
0.072
gMVP
0.83

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-21590704; API