chrX-120560261-TGAGGAGGAG-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PP5BP3BS2

The NM_001079872.2(CUL4B):​c.369_377delCTCCTCCTC​(p.Ser124_Ser126del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 9.26
Variant links:
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 rank MANE Protein UniProt
CUL4BNM_001079872.2 linkc.369_377delCTCCTCCTC p.Ser124_Ser126del disruptive_inframe_deletion Exon 1 of 20 ENST00000371322.11 NP_001073341.1 Q13620-1
CUL4BNM_003588.4 linkc.423_431delCTCCTCCTC p.Ser142_Ser144del disruptive_inframe_deletion Exon 3 of 22 NP_003579.3 Q13620-2
CUL4BNM_001330624.2 linkc.384_392delCTCCTCCTC p.Ser129_Ser131del disruptive_inframe_deletion Exon 2 of 21 NP_001317553.1 K4DI93

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUL4BENST00000371322.11 linkc.369_377delCTCCTCCTC p.Ser124_Ser126del disruptive_inframe_deletion Exon 1 of 20 1 NM_001079872.2 ENSP00000360373.5 Q13620-1
CUL4BENST00000681206.1 linkc.384_392delCTCCTCCTC p.Ser129_Ser131del disruptive_inframe_deletion Exon 2 of 23 ENSP00000505480.1 A0A7P0T954
CUL4BENST00000680673.1 linkc.423_431delCTCCTCCTC p.Ser142_Ser144del disruptive_inframe_deletion Exon 3 of 22 ENSP00000505084.1 Q13620-2
CUL4BENST00000681253.1 linkc.423_431delCTCCTCCTC p.Ser142_Ser144del disruptive_inframe_deletion Exon 4 of 23 ENSP00000506259.1 Q13620-2
CUL4BENST00000681652.1 linkc.423_431delCTCCTCCTC p.Ser142_Ser144del disruptive_inframe_deletion Exon 6 of 25 ENSP00000505176.1 Q13620-2
CUL4BENST00000336592.11 linkc.384_392delCTCCTCCTC p.Ser129_Ser131del disruptive_inframe_deletion Exon 2 of 21 5 ENSP00000338919.6 K4DI93
CUL4BENST00000674137.11 linkc.369_377delCTCCTCCTC p.Ser124_Ser126del disruptive_inframe_deletion Exon 1 of 20 ENSP00000501019.6 A0A669KAX4
CUL4BENST00000681090.1 linkc.369_377delCTCCTCCTC p.Ser124_Ser126del disruptive_inframe_deletion Exon 1 of 20 ENSP00000506288.1 A0A7P0TAQ3
CUL4BENST00000404115.8 linkc.369_377delCTCCTCCTC p.Ser124_Ser126del disruptive_inframe_deletion Exon 1 of 19 1 ENSP00000384109.4 A0A804CL36
CUL4BENST00000679927.1 linkc.24_32delCTCCTCCTC p.Ser9_Ser11del disruptive_inframe_deletion Exon 2 of 21 ENSP00000505603.1 A0A7P0T9L3
CUL4BENST00000673919.1 linkn.369_377delCTCCTCCTC non_coding_transcript_exon_variant Exon 1 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000679432.1 linkn.354_362delCTCCTCCTC non_coding_transcript_exon_variant Exon 1 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000681333.1 linkn.369_377delCTCCTCCTC non_coding_transcript_exon_variant Exon 1 of 17 ENSP00000505739.1 A0A7P0T9R8

Frequencies

GnomAD3 genomes
AF:
0.0000631
AC:
7
AN:
111015
Hom.:
0
Cov.:
22
AF XY:
0.0000300
AC XY:
1
AN XY:
33341
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000958
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000113
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000231
AC:
4
AN:
173145
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
61627
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000514
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000428
AC:
47
AN:
1097200
Hom.:
0
AF XY:
0.0000413
AC XY:
15
AN XY:
362924
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000559
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000631
AC:
7
AN:
111015
Hom.:
0
Cov.:
22
AF XY:
0.0000300
AC XY:
1
AN XY:
33341
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.0000958
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000113
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:1Uncertain:2
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingGeneDxJan 31, 2018The 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 submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 26, 2019In 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. 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. This variant is present in population databases (rs756411375, ExAC 0.004%), including at least one homozygous and/or hemizygous individual. 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). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. -
CUL4B-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 31, 2024The CUL4B c.423_431del9 variant is predicted to result in an in-frame deletion (p.Ser144_Ser146del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754330779; hg19: chrX-119694116; API