X-120530206-ACTGT-A

Position:

• chrX-120530206-ACTGT-A

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.2484_2487delACAG​(p.Arg828fs) 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: 22)
• Consequence: CUL4B NM_001079872.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60

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 0.0759 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-120530206-ACTGT-A is Pathogenic according to our data. Variant chrX-120530206-ACTGT-A is described in ClinVar as [Pathogenic]. Clinvar id is 3364508.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-120530206-ACTGT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2484_2487delACAG	p.Arg828fs	frameshift_variant	19/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2538_2541delACAG	p.Arg846fs	frameshift_variant	21/22		NP_003579.3
CUL4B	NM_001330624.2	c.2499_2502delACAG	p.Arg833fs	frameshift_variant	20/21		NP_001317553.1
CUL4B	NM_001369145.1	c.1950_1953delACAG	p.Arg650fs	frameshift_variant	19/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2484_2487delACAG	p.Arg828fs	frameshift_variant	19/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2598_2601delACAG	p.Arg866fs	frameshift_variant	22/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2538_2541delACAG	p.Arg846fs	frameshift_variant	21/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2538_2541delACAG	p.Arg846fs	frameshift_variant	22/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2538_2541delACAG	p.Arg846fs	frameshift_variant	24/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2499_2502delACAG	p.Arg833fs	frameshift_variant	20/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2490_2493delACAG	p.Arg830fs	frameshift_variant	19/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2391_2394delACAG	p.Arg797fs	frameshift_variant	19/20			ENSP00000506288.1
CUL4B	ENST00000679927.1	c.2139_2142delACAG	p.Arg713fs	frameshift_variant	20/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1950_1953delACAG	p.Arg650fs	frameshift_variant	19/20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1926_1929delACAG	p.Arg642fs	frameshift_variant	18/20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1821_1824delACAG	p.Arg607fs	frameshift_variant	17/18			ENSP00000505239.1
CUL4B	ENST00000404115.8	c.2439+2212_2439+2215delACAG		intron_variant		1		ENSP00000384109.4
CUL4B	ENST00000673919.1	n.*1931_*1934delACAG		non_coding_transcript_exon_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*40_*43delACAG		non_coding_transcript_exon_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1693_*1696delACAG		non_coding_transcript_exon_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1693_*1696delACAG		non_coding_transcript_exon_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1400_*1403delACAG		non_coding_transcript_exon_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1693_*1696delACAG		non_coding_transcript_exon_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*650_*653delACAG		non_coding_transcript_exon_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3377_*3380delACAG		non_coding_transcript_exon_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*656_*659delACAG		non_coding_transcript_exon_variant	19/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1931_*1934delACAG		3_prime_UTR_variant	20/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*40_*43delACAG		3_prime_UTR_variant	17/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1693_*1696delACAG		3_prime_UTR_variant	21/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1693_*1696delACAG		3_prime_UTR_variant	21/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1400_*1403delACAG		3_prime_UTR_variant	17/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1693_*1696delACAG		3_prime_UTR_variant	19/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*650_*653delACAG		3_prime_UTR_variant	19/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3377_*3380delACAG		3_prime_UTR_variant	16/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*656_*659delACAG		3_prime_UTR_variant	19/20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 15, 2024

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29302074) -

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119664061;