X-119841205-TTTTC-T
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_080632.3(UPF3B):c.674_677delGAAA(p.Arg225LysfsTer22) variant causes a frameshift change. The variant allele was found at a frequency of 0.00000505 in 1,188,318 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_080632.3 frameshift
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
UPF3B | ENST00000276201.7 | c.674_677delGAAA | p.Arg225LysfsTer22 | frameshift_variant | Exon 7 of 11 | 1 | NM_080632.3 | ENSP00000276201.3 | ||
UPF3B | ENST00000345865.6 | c.674_677delGAAA | p.Arg225LysfsTer22 | frameshift_variant | Exon 7 of 10 | 1 | ENSP00000245418.2 | |||
UPF3B | ENST00000478840.1 | n.262_265delGAAA | non_coding_transcript_exon_variant | Exon 4 of 6 | 3 |
Frequencies
GnomAD3 genomes AF: 0.0000180 AC: 2AN: 111417Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33587
GnomAD4 exome AF: 0.00000371 AC: 4AN: 1076901Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 344727
GnomAD4 genome AF: 0.0000180 AC: 2AN: 111417Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33587
ClinVar
Submissions by phenotype
Syndromic X-linked intellectual disability 14 Pathogenic:5
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This sequence change creates a premature translational stop signal (p.Arg225Lysfs*22) in the UPF3B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in UPF3B are known to be pathogenic (PMID: 17704778, 19238151). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with UPF3B-related conditions (PMID: 17704778). It has also been observed to segregate with disease in related individuals. This variant is also known as 674_677delGAAA and/or R225fs*20. ClinVar contains an entry for this variant (Variation ID: 198608). For these reasons, this variant has been classified as Pathogenic. -
The p.Arg225Lysfs*22 variant in the UPF3B gene has been reported de novo in 1 individual and maternally inherited in 4 additional unrelated individuals (GeneDx, personal communication, January 17, 2020; Tarpey et al., 2007). In one family the variant co-segregated with disease between siblings. All of these individuals were hemizygous males who presented features consistent with UPF3B-associated intellectual disability disorder. The p.Arg225Lysfs*22 variant results in a 4 bp deletion, which causes a shift in the protein reading frame, leading to a premature termination codon 22 amino acids downstream. Hemizygous loss of function is an established mechanism of disease for the UPF3B gene.The variant is absent from large population databases, including the Genome Aggregation Database (http://gnomad.broadinstitute.org/). These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, there is sufficient evidence to classify the p.Arg225Lysfs*22 variant as pathogenic for X-linked UPF3B-associated intellectual disability disorder based on the information above. [ACMG evidence codes used: PVS1; PS2_supporting; PS4_supporting; PM2_supporting] -
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Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with intellectual developmental disorder, X-linked syndromic 14 (MIM#300676). (I) 0109 - This gene is associated with X-linked recessive disease. (I) 0201 - Variant is predicted to cause nonsense-mediated decay (NMD) and loss of protein (premature termination codon is located at least 54 nucleotides upstream of the final exon-exon junction). (SP) 0253 - This variant is hemizygous. (I) 0304 - Variant is present in gnomAD (v3) <0.01 for a recessive condition (2 heterozygotes, 0 homozygotes, 0 hemizygotes). (SP) 0701 - Many other NMD-predicted variants comparable to the one identified in this case have very strong previous evidence for pathogenicity (DECIPHER). (SP) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as pathogenic by multiple clinical laboratories in ClinVar. (SP) 1205 - This variant has been shown to be maternally inherited (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
not provided Pathogenic:3
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 at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17704778, 26012578, 19377476, 24665081) -
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UPF3B-associated intellectual disability Other:1
Variant interpreted as Pathogenic and reported on 09-10-2020 by Lab or GTR ID Stanford Children's Hospital. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at