rs122468181
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Variant summary
Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_StrongPM2PP5_Moderate
The NM_080632.3(UPF3B):c.1288C>T(p.Arg430Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. R430R) has been classified as Likely benign.
Frequency
Genomes: 𝑓 0.0 ( 0 hom., 0 hem., cov: 22)
Failed GnomAD Quality Control
Consequence
UPF3B
NM_080632.3 stop_gained
NM_080632.3 stop_gained
Scores
3
1
1
Clinical Significance
Conservation
PhyloP100: 7.21
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 Likely_pathogenic. Variant got 8 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. Fraction of 0.113 CDS is truncated, and there are 1 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-119837771-G-A is Pathogenic according to our data. Variant chrX-119837771-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11400.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-119837771-G-A is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UPF3B | NM_080632.3 | c.1288C>T | p.Arg430Ter | stop_gained | 10/11 | ENST00000276201.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UPF3B | ENST00000276201.7 | c.1288C>T | p.Arg430Ter | stop_gained | 10/11 | 1 | NM_080632.3 | A1 | |
UPF3B | ENST00000345865.6 | c.1249C>T | p.Arg417Ter | stop_gained | 9/10 | 1 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00 AC: 0AN: 111338Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33542 FAILED QC
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GnomAD4 exome Cov.: 31
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GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 111338Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33542
GnomAD4 genome
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability 14 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 01, 2013 | - - |
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2023 | Nonsense variant predicted to result in protein truncation, as the last 54 amino acids are lost, and other loss-of-function variants have been reported downstream in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704778, 22957832, 19377476, 25525159, 26012578, 34356170, 33004838) - |
Computational scores
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Name
Calibrated prediction
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BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
FATHMM_MKL
Pathogenic
D
MutationTaster
Benign
A;A
Vest4
GERP RS
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