rs1064794254
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_080632.3(UPF3B):c.697_698del(p.Arg233GlufsTer32) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 22)
Consequence
UPF3B
NM_080632.3 frameshift
NM_080632.3 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 5.86
Genes affected
UPF3B (HGNC:20439): (UPF3B regulator of nonsense mediated mRNA decay) This gene encodes a protein that is part of a post-splicing multiprotein complex involved in both mRNA nuclear export and mRNA surveillance. The encoded protein is one of two functional homologs to yeast Upf3p. mRNA surveillance detects exported mRNAs with truncated open reading frames and initiates nonsense-mediated mRNA decay (NMD). When translation ends upstream from the last exon-exon junction, this triggers NMD to degrade mRNAs containing premature stop codons. This protein binds to the mRNA and remains bound after nuclear export, acting as a nucleocytoplasmic shuttling protein. It forms with Y14 a complex that binds specifically 20 nt upstream of exon-exon junctions. This gene is located on the long arm of chromosome X. Two splice variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]
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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 X-119841184-CCT-C is Pathogenic according to our data. Variant chrX-119841184-CCT-C is described in ClinVar as [Pathogenic]. Clinvar id is 420043.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UPF3B | NM_080632.3 | c.697_698del | p.Arg233GlufsTer32 | frameshift_variant | 7/11 | ENST00000276201.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UPF3B | ENST00000276201.7 | c.697_698del | p.Arg233GlufsTer32 | frameshift_variant | 7/11 | 1 | NM_080632.3 | A1 | |
UPF3B | ENST00000345865.6 | c.697_698del | p.Arg233GlufsTer32 | frameshift_variant | 7/10 | 1 | P4 | ||
UPF3B | ENST00000478840.1 | n.285_286del | non_coding_transcript_exon_variant | 4/6 | 3 |
Frequencies
GnomAD3 genomes ? Cov.: 22
GnomAD3 genomes
?
Cov.:
22
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome ? Cov.: 22
GnomAD4 genome
?
Cov.:
22
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability 14 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing;provider interpretation | Geisinger Autism and Developmental Medicine Institute, Geisinger Health System | Mar 28, 2017 | This 2 year old male with global developmental delays, autism spectrum disorder, large stature, and macrocephaly was found to carry a maternally inherited frameshift variant in the UPF3B gene. The patient also has dolicocephaly, wide nasal bridge, epicanthal folds, full lips, and a wide mouth. The patient's mother is unaffected. The patient's maternal great-uncle was found to harbor the same variant; he has an intellectual disability and reported macrocephaly. The c.697_698delAG variant in the UPF3B gene has been reported previously in two brothers, both with developmental delay and renal dysplasia, and one also with macrocephaly (Lynch et al., 2012). The c.697_698delAG variant causes a frameshift and is predicted to cause loss of normal protein function either through protein truncation or nonsense-mediated mRNA decay. The variant is absent from population databases. - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 15, 2019 | Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 22609145) - |
Computational scores
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Calibrated prediction
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Prediction
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