X-120530154-CTAAG-C

Position:

• chrX-120530154-CTAAG-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001079872.2(CUL4B):​c.2536_2539delCTTA​(p.Leu846fs) 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 O:1
• Conservation: PhyloP100: 8.95

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]

ACMG classification

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/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2536_2539delCTTA	p.Leu846fs	frameshift_variant	19/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2590_2593delCTTA	p.Leu864fs	frameshift_variant	21/22		NP_003579.3
CUL4B	NM_001330624.2	c.2551_2554delCTTA	p.Leu851fs	frameshift_variant	20/21		NP_001317553.1
CUL4B	NM_001369145.1	c.2002_2005delCTTA	p.Leu668fs	frameshift_variant	19/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2536_2539delCTTA	p.Leu846fs	frameshift_variant	19/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2650_2653delCTTA	p.Leu884fs	frameshift_variant	22/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2590_2593delCTTA	p.Leu864fs	frameshift_variant	21/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2590_2593delCTTA	p.Leu864fs	frameshift_variant	22/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2590_2593delCTTA	p.Leu864fs	frameshift_variant	24/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2551_2554delCTTA	p.Leu851fs	frameshift_variant	20/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2542_2545delCTTA	p.Leu848fs	frameshift_variant	19/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2443_2446delCTTA	p.Leu815fs	frameshift_variant	19/20			ENSP00000506288.1
CUL4B	ENST00000679927.1	c.2191_2194delCTTA	p.Leu731fs	frameshift_variant	20/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2002_2005delCTTA	p.Leu668fs	frameshift_variant	19/20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1978_1981delCTTA	p.Leu660fs	frameshift_variant	18/20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1873_1876delCTTA	p.Leu625fs	frameshift_variant	17/18			ENSP00000505239.1
CUL4B	ENST00000404115.8	c.2439+2264_2439+2267delCTTA		intron_variant		1		ENSP00000384109.4
CUL4B	ENST00000673919.1	n.*1983_*1986delCTTA		non_coding_transcript_exon_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*92_*95delCTTA		non_coding_transcript_exon_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1745_*1748delCTTA		non_coding_transcript_exon_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1745_*1748delCTTA		non_coding_transcript_exon_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1452_*1455delCTTA		non_coding_transcript_exon_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1745_*1748delCTTA		non_coding_transcript_exon_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*702_*705delCTTA		non_coding_transcript_exon_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3429_*3432delCTTA		non_coding_transcript_exon_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*708_*711delCTTA		non_coding_transcript_exon_variant	19/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1983_*1986delCTTA		3_prime_UTR_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*92_*95delCTTA		3_prime_UTR_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1745_*1748delCTTA		3_prime_UTR_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1745_*1748delCTTA		3_prime_UTR_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1452_*1455delCTTA		3_prime_UTR_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1745_*1748delCTTA		3_prime_UTR_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*702_*705delCTTA		3_prime_UTR_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3429_*3432delCTTA		3_prime_UTR_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*708_*711delCTTA		3_prime_UTR_variant	19/20			ENSP00000505777.1

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:1 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Oct 17, 2024

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

not provided, no classification provided

phenotyping only

GenomeConnect - Brain Gene Registry

-

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

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

Other links and lift over

dbSNP: rs1602567594; hg19: chrX-119664009;