rs762218403
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_006907.4(PYCR1):c.59_60insC(p.Ala21SerfsTer13) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000199 in 1,608,500 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000021 ( 0 hom. )
Consequence
PYCR1
NM_006907.4 frameshift
NM_006907.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 4.92
Genes affected
PYCR1 (HGNC:9721): (pyrroline-5-carboxylate reductase 1) This gene encodes an enzyme that catalyzes the NAD(P)H-dependent conversion of pyrroline-5-carboxylate to proline. This enzyme may also play a physiologic role in the generation of NADP(+) in some cell types. The protein forms a homopolymer and localizes to the mitochondrion. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 41 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-81936755-T-TG is Pathogenic according to our data. Variant chr17-81936755-T-TG is described in ClinVar as [Pathogenic]. Clinvar id is 488457.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PYCR1 | NM_006907.4 | c.59_60insC | p.Ala21SerfsTer13 | frameshift_variant | 1/7 | ENST00000329875.13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PYCR1 | ENST00000329875.13 | c.59_60insC | p.Ala21SerfsTer13 | frameshift_variant | 1/7 | 1 | NM_006907.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000126 AC: 3AN: 237756Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 129392
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GnomAD4 exome AF: 0.0000213 AC: 31AN: 1456284Hom.: 0 Cov.: 31 AF XY: 0.0000152 AC XY: 11AN XY: 723960
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GnomAD4 genome AF: 0.00000657 AC: 1AN: 152216Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74370
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Autosomal recessive cutis laxa type 2B Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Molecular Genetics Laboratory, BC Children's and BC Women's Hospitals | Jul 24, 2017 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 24, 2022 | For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 488457). This variant has not been reported in the literature in individuals affected with PYCR1-related conditions. This variant is present in population databases (rs762218403, gnomAD 0.003%). This sequence change creates a premature translational stop signal (p.Ala21Serfs*13) in the PYCR1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PYCR1 are known to be pathogenic (PMID: 19648921). - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at