rs606231196
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Variant summary
Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong
The NM_001032382.2(PQBP1):c.640dup(p.Arg214ProfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: not found (cov: 21)
Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )
Failed GnomAD Quality Control
Consequence
PQBP1
NM_001032382.2 frameshift
NM_001032382.2 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 6.81
Genes affected
PQBP1 (HGNC:9330): (polyglutamine binding protein 1) This gene encodes a nuclear polyglutamine-binding protein that is involved with transcription activation. The encoded protein contains a WW domain. Mutations in this gene have been found in patients with Renpenning syndrome 1 and other syndromes with X-linked cognitive disability. Multiple alternatively spliced transcript variants that encode different protein isoforms have been described for this gene.[provided by RefSeq, Nov 2009]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 14 ACMG points.
PVS1
?
Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant X-48902788-G-GC is Pathogenic according to our data. Variant chrX-48902788-G-GC is described in ClinVar as [Pathogenic]. Clinvar id is 10982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
PQBP1 | NM_001032382.2 | c.640dup | p.Arg214ProfsTer13 | frameshift_variant | 6/7 | ENST00000447146.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
PQBP1 | ENST00000447146.7 | c.640dup | p.Arg214ProfsTer13 | frameshift_variant | 6/7 | 1 | NM_001032382.2 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 21
GnomAD3 genomes
?
Cov.:
21
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1088506Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 356216
GnomAD4 exome
Data not reliable, filtered out with message: AC0
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1088506
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33
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356216
Gnomad4 AFR exome
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GnomAD4 genome ? Cov.: 21
GnomAD4 genome
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Cov.:
21
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Renpenning syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Feb 05, 2013 | This variant has been previously reported as disease-causing and was found once in our laboratory maternally inherited in a 40-year-old male with intellectual disability, autism, dysmorphic features, strabismus - |
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 01, 2004 | - - |
Pathogenic, criteria provided, single submitter | research | Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center | - | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Oct 24, 2018 | The c.640dupC variant in the PQBP1 gene, reported as c.641insC due to use of alternative nomenclature, segregates with Renpenning syndrome in multiple affected male individuals from a single family in published literature (Lenski et al., 2004). The c.640dupC variant causes a frameshift starting with codon Arginine 214, changes this amino acid to a Proline residue, and creates a premature Stop codon at position 13 of the new reading frame, denoted p.Arg214ProfsX13. This variant is predicted to cause loss of normal protein function through protein truncation as the last 52 amino acids of the protein are lost and replaced with 12 incorrect amino acids. The c.640dupC variant is not observed in large population cohorts (Lek et al., 2016). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jun 01, 2021 | - - |
Computational scores
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Splicing
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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