X-120530154-CTAAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_ModeratePM2PP5_Moderate

The NM_001079872.2(CUL4B):​c.2536_2539delCTTA​(p.Leu846AlafsTer13) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Consequence

CUL4B
NM_001079872.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, single submitter P:1O:1

Conservation

PhyloP100: 8.95
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_pathogenic. Variant got 6 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 0.0565 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant X-120530154-CTAAG-C is Pathogenic according to our data. Variant chrX-120530154-CTAAG-C is described in ClinVar as [Pathogenic]. Clinvar id is 817034.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-120530154-CTAAG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CUL4BNM_001079872.2 linkc.2536_2539delCTTA p.Leu846AlafsTer13 frameshift_variant Exon 19 of 20 ENST00000371322.11 NP_001073341.1 Q13620-1
CUL4BNM_003588.4 linkc.2590_2593delCTTA p.Leu864AlafsTer13 frameshift_variant Exon 21 of 22 NP_003579.3 Q13620-2
CUL4BNM_001330624.2 linkc.2551_2554delCTTA p.Leu851AlafsTer13 frameshift_variant Exon 20 of 21 NP_001317553.1 K4DI93
CUL4BNM_001369145.1 linkc.2002_2005delCTTA p.Leu668AlafsTer13 frameshift_variant Exon 19 of 20 NP_001356074.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CUL4BENST00000371322.11 linkc.2536_2539delCTTA p.Leu846AlafsTer13 frameshift_variant Exon 19 of 20 1 NM_001079872.2 ENSP00000360373.5 Q13620-1
CUL4BENST00000681206.1 linkc.2650_2653delCTTA p.Leu884AlafsTer13 frameshift_variant Exon 22 of 23 ENSP00000505480.1 A0A7P0T954
CUL4BENST00000680673.1 linkc.2590_2593delCTTA p.Leu864AlafsTer13 frameshift_variant Exon 21 of 22 ENSP00000505084.1 Q13620-2
CUL4BENST00000681253.1 linkc.2590_2593delCTTA p.Leu864AlafsTer13 frameshift_variant Exon 22 of 23 ENSP00000506259.1 Q13620-2
CUL4BENST00000681652.1 linkc.2590_2593delCTTA p.Leu864AlafsTer13 frameshift_variant Exon 24 of 25 ENSP00000505176.1 Q13620-2
CUL4BENST00000336592.11 linkc.2551_2554delCTTA p.Leu851AlafsTer13 frameshift_variant Exon 20 of 21 5 ENSP00000338919.6 K4DI93
CUL4BENST00000674137.11 linkc.2542_2545delCTTA p.Leu848AlafsTer13 frameshift_variant Exon 19 of 20 ENSP00000501019.6 A0A669KAX4
CUL4BENST00000681090.1 linkc.2443_2446delCTTA p.Leu815AlafsTer13 frameshift_variant Exon 19 of 20 ENSP00000506288.1 A0A7P0TAQ3
CUL4BENST00000679927.1 linkc.2191_2194delCTTA p.Leu731AlafsTer13 frameshift_variant Exon 20 of 21 ENSP00000505603.1 A0A7P0T9L3
CUL4BENST00000371323.3 linkc.2002_2005delCTTA p.Leu668AlafsTer13 frameshift_variant Exon 19 of 20 5 ENSP00000360374.3 Q13620-3
CUL4BENST00000680474.1 linkc.1978_1981delCTTA p.Leu660fs frameshift_variant Exon 18 of 20 ENSP00000505562.1 A0A7P0T9C8
CUL4BENST00000679844.1 linkc.1873_1876delCTTA p.Leu625fs frameshift_variant Exon 17 of 18 ENSP00000505239.1 A0A7P0T8P8
CUL4BENST00000404115.8 linkc.2439+2264_2439+2267delCTTA intron_variant Intron 18 of 18 1 ENSP00000384109.4 A0A804CL36
CUL4BENST00000673919.1 linkn.*1983_*1986delCTTA non_coding_transcript_exon_variant Exon 20 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*92_*95delCTTA non_coding_transcript_exon_variant Exon 17 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1745_*1748delCTTA non_coding_transcript_exon_variant Exon 21 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1745_*1748delCTTA non_coding_transcript_exon_variant Exon 21 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1452_*1455delCTTA non_coding_transcript_exon_variant Exon 17 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1745_*1748delCTTA non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*702_*705delCTTA non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3429_*3432delCTTA non_coding_transcript_exon_variant Exon 16 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*708_*711delCTTA non_coding_transcript_exon_variant Exon 19 of 20 ENSP00000505777.1 A0A7P0T9P5
CUL4BENST00000673919.1 linkn.*1983_*1986delCTTA 3_prime_UTR_variant Exon 20 of 21 ENSP00000500994.1 A0A669KAU9
CUL4BENST00000674073.2 linkn.*92_*95delCTTA 3_prime_UTR_variant Exon 17 of 18 ENSP00000501262.2 A0A669KBG9
CUL4BENST00000679405.1 linkn.*1745_*1748delCTTA 3_prime_UTR_variant Exon 21 of 22 ENSP00000504985.1 A0A7P0Z439
CUL4BENST00000679432.1 linkn.*1745_*1748delCTTA 3_prime_UTR_variant Exon 21 of 22 ENSP00000505343.1 A0A7P0T8W4
CUL4BENST00000680918.1 linkn.*1452_*1455delCTTA 3_prime_UTR_variant Exon 17 of 18 ENSP00000505955.1 A0A7P0Z4G9
CUL4BENST00000681080.1 linkn.*1745_*1748delCTTA 3_prime_UTR_variant Exon 19 of 20 ENSP00000505898.1 A0A7P0Z4E4
CUL4BENST00000681189.1 linkn.*702_*705delCTTA 3_prime_UTR_variant Exon 19 of 20 ENSP00000505973.1 A0A7P0TAF9
CUL4BENST00000681333.1 linkn.*3429_*3432delCTTA 3_prime_UTR_variant Exon 16 of 17 ENSP00000505739.1 A0A7P0T9R8
CUL4BENST00000681908.1 linkn.*708_*711delCTTA 3_prime_UTR_variant Exon 19 of 20 ENSP00000505777.1 A0A7P0T9P5

Frequencies

GnomAD3 genomes
Cov.:
23
We have no GnomAD4 exomes data on this position. Probably position not covered by the project.
GnomAD4 genome
Cov.:
23

ClinVar

Significance: Pathogenic
Submissions summary: Pathogenic:1Other:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Pathogenic:1
Oct 17, 2024
GeneDx
Significance: Pathogenic
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Frameshift variant predicted to result in abnormal protein length as the last 50 amino acid(s) are replaced with 12 different amino acid(s), and other similar variants have been reported in HGMD; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25385192) -

CUL4B-related disorder Other:1
-
GenomeConnect - Brain Gene Registry
Significance: not provided
Review Status: no classification provided
Collection Method: phenotyping only

Variant interpreted as Likely pathogenic and reported on 10-13-2018 by GeneDx. Assertions are reported exactly as they appear on the patient provided laboratory report. GenomeConnect does not attempt to reinterpret the variant. The IDDRC-CTSA National Brain Gene Registry (BGR) is a study funded by the U.S. National Center for Advancing Translational Sciences (NCATS) and includes 13 Intellectual and Developmental Disability Research Center (IDDRC) institutions. The study is led by Principal Investigator Philip Payne PhD, FACMI from Washington University. The BGR is a data commons of gene variants paired with subject clinical information. This database helps scientists learn more about genetic changes and their impact on the brain and behavior. Participation in the Brain Gene Registry requires participation in GenomeConnect. More information about the Brain Gene Registry can be found on the study website - https://braingeneregistry.wustl.edu/. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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: rs1602567594; hg19: chrX-119664009; API