rs878853260
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Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_002582.4(PARN):c.563_564insT(p.Glu189ArgfsTer7) variant causes a frameshift change. The variant allele was found at a frequency of 0.000000737 in 1,356,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 7.4e-7 ( 0 hom. )
Consequence
PARN
NM_002582.4 frameshift
NM_002582.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.72
Genes affected
PARN (HGNC:8609): (poly(A)-specific ribonuclease) The protein encoded by this gene is a 3'-exoribonuclease, with similarity to the RNase D family of 3'-exonucleases. It prefers poly(A) as the substrate, hence, efficiently degrades poly(A) tails of mRNAs. Exonucleolytic degradation of the poly(A) tail is often the first step in the decay of eukaryotic mRNAs. This protein is also involved in silencing of certain maternal mRNAs during oocyte maturation and early embryonic development, as well as in nonsense-mediated decay (NMD) of mRNAs that contain premature stop codons. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 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 16-14609114-T-TA is Pathogenic according to our data. Variant chr16-14609114-T-TA is described in ClinVar as [Pathogenic]. Clinvar id is 190470.Status of the report is criteria_provided_single_submitter, 1 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PARN | NM_002582.4 | c.563_564insT | p.Glu189ArgfsTer7 | frameshift_variant | 8/24 | ENST00000437198.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PARN | ENST00000437198.7 | c.563_564insT | p.Glu189ArgfsTer7 | frameshift_variant | 8/24 | 1 | NM_002582.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
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32
GnomAD4 exome AF: 7.37e-7 AC: 1AN: 1356298Hom.: 0 Cov.: 21 AF XY: 0.00 AC XY: 0AN XY: 675982
GnomAD4 exome
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GnomAD4 genome ? Cov.: 32
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Bravo
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Pulmonary fibrosis Pathogenic:1
Likely risk allele, no assertion criteria provided | research | Garcia Pulmonary Genetics Research Laboratory, Columbia University Irving Medical Center | Jun 09, 2022 | - - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | May 01, 2015 | - - |
Pulmonary fibrosis and/or bone marrow failure, Telomere-related, 4;C4225356:Dyskeratosis congenita, autosomal recessive 6 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Nov 24, 2023 | This sequence change creates a premature translational stop signal (p.Glu189Argfs*7) in the PARN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in PARN are known to be pathogenic (PMID: 9736620, 25848748, 26810774). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with familial pulmonary fibrosis (PMID: 25848748). This variant is also known as c.563_564insT (Ile188Ilefs*7). ClinVar contains an entry for this variant (Variation ID: 190470). For these reasons, this variant has been classified as Pathogenic. - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at