chr8-143818041-GGCTGGGCCTGCCCTATGTT-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_078480.3(PUF60):c.619_637del(p.Asn207ProfsTer3) 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Consequence
PUF60
NM_078480.3 frameshift
NM_078480.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.30
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 Pathogenic. Variant got 18 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 8-143818041-GGCTGGGCCTGCCCTATGTT-G is Pathogenic according to our data. Variant chr8-143818041-GGCTGGGCCTGCCCTATGTT-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 425573.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-143818041-GGCTGGGCCTGCCCTATGTT-G is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PUF60 | NM_078480.3 | c.619_637del | p.Asn207ProfsTer3 | frameshift_variant | 8/12 | ENST00000526683.6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PUF60 | ENST00000526683.6 | c.619_637del | p.Asn207ProfsTer3 | frameshift_variant | 8/12 | 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: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 24, 2018 | The c.619_637del19 variant in the PUF60 gene has been reported previously as a de novo variant with confirmed parentage in a patient with intellectual disability, developmental delay, microcephaly, horseshoe kidney, truncus arteriosus, submucous cleft palate and dysmorphic features (Low et al., 2017). This variant is not observed in large population cohorts (Lek et al., 2016). The c.619_637del19 variant causes a frameshift starting with codon Asparagine 207, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 3 of the new reading frame, denoted p.Asn207ProfsX3. This variant is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. We interpret c.619_637del19 as a pathogenic variant. - |
Likely pathogenic, criteria provided, single submitter | research | Bristol Genetics Laboratory, North Bristol NHS Trust | Jan 19, 2017 | - - |
8q24.3 microdeletion syndrome Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jun 01, 2016 | This variant was identified as de novo (maternity and paternity confirmed). - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at