X-120526810-TAG-T

Variant names:

• chrX-120526810-TAG-T
• rs1057518598
• NM_001079872.2:c.2637_2638delCT

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.2637_2638delCT​(p.Asp879GlufsTer6) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.94

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 exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.019 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-120526810-TAG-T is Pathogenic according to our data. Variant chrX-120526810-TAG-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 373768.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2637_2638delCT	p.Asp879GlufsTer6	frameshift_variant	Exon 20 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2691_2692delCT	p.Asp897GlufsTer6	frameshift_variant	Exon 22 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2652_2653delCT	p.Asp884GlufsTer6	frameshift_variant	Exon 21 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.2103_2104delCT	p.Asp701GlufsTer6	frameshift_variant	Exon 20 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2637_2638delCT	p.Asp879GlufsTer6	frameshift_variant	Exon 20 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2751_2752delCT	p.Asp917GlufsTer6	frameshift_variant	Exon 23 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2691_2692delCT	p.Asp897GlufsTer6	frameshift_variant	Exon 22 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2691_2692delCT	p.Asp897GlufsTer6	frameshift_variant	Exon 23 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2691_2692delCT	p.Asp897GlufsTer6	frameshift_variant	Exon 25 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2652_2653delCT	p.Asp884GlufsTer6	frameshift_variant	Exon 21 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2643_2644delCT	p.Asp881GlufsTer6	frameshift_variant	Exon 20 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2544_2545delCT	p.Asp848GlufsTer6	frameshift_variant	Exon 20 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2484_2485delCT	p.Asp828GlufsTer6	frameshift_variant	Exon 19 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2292_2293delCT	p.Asp764GlufsTer6	frameshift_variant	Exon 21 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2103_2104delCT	p.Asp701GlufsTer6	frameshift_variant	Exon 20 of 20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.1974_1975delCT	p.Asp658fs	frameshift_variant	Exon 18 of 18			ENSP00000505239.1
CUL4B	ENST00000680474	c.*83_*84delCT		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2084_*2085delCT		non_coding_transcript_exon_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*193_*194delCT		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1846_*1847delCT		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1846_*1847delCT		non_coding_transcript_exon_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1553_*1554delCT		non_coding_transcript_exon_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1846_*1847delCT		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*803_*804delCT		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3530_*3531delCT		non_coding_transcript_exon_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*809_*810delCT		non_coding_transcript_exon_variant	Exon 20 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2084_*2085delCT		3_prime_UTR_variant	Exon 21 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*193_*194delCT		3_prime_UTR_variant	Exon 18 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1846_*1847delCT		3_prime_UTR_variant	Exon 22 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1846_*1847delCT		3_prime_UTR_variant	Exon 22 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1553_*1554delCT		3_prime_UTR_variant	Exon 18 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1846_*1847delCT		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*803_*804delCT		3_prime_UTR_variant	Exon 20 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3530_*3531delCT		3_prime_UTR_variant	Exon 17 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*809_*810delCT		3_prime_UTR_variant	Exon 20 of 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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Dec 05, 2016

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2691_2692delCT variant in the CUL4B gene has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The c.2691_2692delCT variant causes a frameshift starting with codon Aspartic acid 897, changes this amino acid to a Glutamic acid residue, and creates a premature Stop codon at position 6 of the new reading frame, denoted p.Asp897GlufsX6. This variant replaces the last 17 amino acids by 5 incorrect amino acids and is predicted to cause loss of normal protein function through protein truncation. The c.2691_2692delCT variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, we interpret c.2691_2692delCT as a likely pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1057518598; hg19: chrX-119660665;