rs754330779
Variant summary
Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PP5BP3BS2
The NM_001079872.2(CUL4B):c.369_377del(p.Ser126_Ser128del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 22)
Exomes 𝑓: 0.000043 ( 0 hom. 15 hem. )
Consequence
CUL4B
NM_001079872.2 inframe_deletion
NM_001079872.2 inframe_deletion
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 9.26
Genes affected
CUL4B (HGNC:2555): (cullin 4B) This gene is a member of the cullin family. The encoded protein forms a complex that functions as an E3 ubiquitin ligase and catalyzes the polyubiquitination of specific protein substrates in the cell. The protein interacts with a ring finger protein, and is required for the proteolysis of several regulators of DNA replication including chromatin licensing and DNA replication factor 1 and cyclin E. Multiple transcript 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.
PP3
?
No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
PP5
?
Variant X-120560261-TGAGGAGGAG-T is Pathogenic according to our data. Variant chrX-120560261-TGAGGAGGAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504176.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.
BP3
?
Nonframeshift variant in repetitive region in NM_001079872.2
BS2
?
High Hemizygotes in GnomAdExome4 at 15 XL gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CUL4B | NM_001079872.2 | c.369_377del | p.Ser126_Ser128del | inframe_deletion | 1/20 | ENST00000371322.11 | |
CUL4B | NM_001330624.2 | c.384_392del | p.Ser131_Ser133del | inframe_deletion | 2/21 | ||
CUL4B | NM_003588.4 | c.423_431del | p.Ser144_Ser146del | inframe_deletion | 3/22 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CUL4B | ENST00000371322.11 | c.369_377del | p.Ser126_Ser128del | inframe_deletion | 1/20 | 1 | NM_001079872.2 |
Frequencies
GnomAD3 genomes ? AF: 0.0000631 AC: 7AN: 111015Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1AN XY: 33341
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GnomAD3 exomes AF: 0.0000231 AC: 4AN: 173145Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 61627
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GnomAD4 exome AF: 0.0000428 AC: 47AN: 1097200Hom.: 0 AF XY: 0.0000413 AC XY: 15AN XY: 362924
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:1
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jan 31, 2018 | The c.423_431delCTCCTCCTC variant in the XXX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.423_431delCTCCTCCTC variant causes an inframe deletion of three amino acids starting at Serine 144, denoted p.S144_S146del. The c.423_431delCTCCTCCTC variant is observed in 5/86720 (0.0058%) alleles from individuals of non-Finnish European background, and 5/190079 total alleles in large population cohorts (Lek et al., 2016). We interpret c.423_431delCTCCTCCTC as a likely pathogenic variant. - |
X-linked intellectual disability Cabezas type Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 26, 2019 | 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 for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with CUL4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 504176). This variant is present in population databases (rs756411375, ExAC 0.004%), including at least one homozygous and/or hemizygous individual. This variant, c.423_431del, results in the deletion of 3 amino acid(s) of the CUL4B protein (p.Ser144_Ser146del), but otherwise preserves the integrity of the reading frame. - |
Computational scores
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Find out detailed SpliceAI scores and Pangolin per-transcript scores at