X-119837792-CTTT-C
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Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PM4_SupportingBS2
The NM_080632.3(UPF3B):βc.1264_1266delβ(p.Lys422del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000414 in 1,208,836 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. Variant has been reported in ClinVar as Uncertain significance (β ).
Frequency
Genomes: π 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes π: 0.0000036 ( 0 hom. 2 hem. )
Consequence
UPF3B
NM_080632.3 inframe_deletion
NM_080632.3 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 7.30
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_benign. Variant got -3 ACMG points.
PM4
Nonframeshift variant in NON repetitive region in NM_080632.3. Strenght limited to Supporting due to length of the change: 1aa.
BS2
High Hemizygotes in GnomAdExome4 at 2 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
UPF3B | NM_080632.3 | c.1264_1266del | p.Lys422del | inframe_deletion | 10/11 | ENST00000276201.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
UPF3B | ENST00000276201.7 | c.1264_1266del | p.Lys422del | inframe_deletion | 10/11 | 1 | NM_080632.3 | A1 | |
UPF3B | ENST00000345865.6 | c.1225_1227del | p.Lys409del | inframe_deletion | 9/10 | 1 | P4 |
Frequencies
GnomAD3 genomes AF: 0.00000897 AC: 1AN: 111479Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33675
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GnomAD3 exomes AF: 0.0000110 AC: 2AN: 181867Hom.: 0 AF XY: 0.0000150 AC XY: 1AN XY: 66505
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GnomAD4 exome AF: 0.00000365 AC: 4AN: 1097357Hom.: 0 AF XY: 0.00000551 AC XY: 2AN XY: 362877
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GnomAD4 genome AF: 0.00000897 AC: 1AN: 111479Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0AN XY: 33675
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Syndromic X-linked intellectual disability 14 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 18, 2022 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. This variant has not been reported in the literature in individuals affected with UPF3B-related conditions. This variant is present in population databases (rs778553900, gnomAD 0.02%), including at least one homozygous and/or hemizygous individual. This variant, c.1264_1266del, results in the deletion of 1 amino acid(s) of the UPF3B protein (p.Lys422del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at