chr8-143816525-CAG-C
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_StrongPM2
The NM_078480.3(PUF60):c.1673_1674del(p.Ser558CysfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: not found (cov: 32)
Consequence
PUF60
NM_078480.3 frameshift
NM_078480.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.12
Genes affected
PUF60 (HGNC:17042): (poly(U) binding splicing factor 60) This gene encodes a nucleic acid-binding protein that plays a role in a variety of nuclear processes, including pre-mRNA splicing and transcriptional regulation. The encoded protein forms a complex with the far upstream DNA element (FUSE) and FUSE-binding protein at the myelocytomatosis oncogene (MYC) promoter. This complex represses MYC transcription through the core-TFIIH basal transcription factor. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Aug 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.499 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PUF60 | NM_078480.3 | c.1673_1674del | p.Ser558CysfsTer21 | frameshift_variant | 12/12 | ENST00000526683.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PUF60 | ENST00000526683.6 | c.1673_1674del | p.Ser558CysfsTer21 | frameshift_variant | 12/12 | 1 | NM_078480.3 |
Frequencies
GnomAD3 genomes ? Cov.: 32
GnomAD3 genomes
?
Cov.:
32
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 32
GnomAD4 genome
?
Cov.:
32
ClinVar
Significance: Uncertain significance
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Neurodevelopmental abnormality Pathogenic:1
Likely pathogenic, no assertion criteria provided | clinical testing | Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine | Apr 03, 2020 | - - |
PUF60-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Feb 16, 2024 | The PUF60 c.1673_1674delCT variant is predicted to result in a frameshift and premature protein termination (p.Ser558Cysfs*21). This variant is located within the second to last codon of the transcript and therefore causes a protein extension of 21 amino acids and is not expected to undergo nonsense mediated decay. This variant has been reported as de novo in an individual with mild symptoms of Verheij syndrome (Yamada et al 2020. PubMed ID: 32851780). This same report confirmed that the transcript escaped nonsense mediated decay. This variant has not been reported in a large population database, indicating this variant is rare. Although we suspect that this variant may be pathogenic, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. - |
Computational scores
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Name
Calibrated prediction
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Prediction
Splicing
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Calibrated prediction
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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