rs1556206910

Variant names:

• chrX-120541639-ACT-A
• rs1556206910
• NM_001079872.2:c.1404_1405delAG

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001079872.2(CUL4B):​c.1404_1405delAG​(p.Val469SerfsTer21) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.08

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120541639-ACT-A is Pathogenic according to our data. Variant chrX-120541639-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 523617.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.1404_1405delAG	p.Val469SerfsTer21	frameshift_variant	Exon 10 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1458_1459delAG	p.Val487SerfsTer21	frameshift_variant	Exon 12 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.1419_1420delAG	p.Val474SerfsTer21	frameshift_variant	Exon 11 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.870_871delAG	p.Val291SerfsTer21	frameshift_variant	Exon 10 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1404_1405delAG	p.Val469SerfsTer21	frameshift_variant	Exon 10 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1518_1519delAG	p.Val507SerfsTer21	frameshift_variant	Exon 13 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1458_1459delAG	p.Val487SerfsTer21	frameshift_variant	Exon 12 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1458_1459delAG	p.Val487SerfsTer21	frameshift_variant	Exon 13 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1458_1459delAG	p.Val487SerfsTer21	frameshift_variant	Exon 15 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1419_1420delAG	p.Val474SerfsTer21	frameshift_variant	Exon 11 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1404_1405delAG	p.Val469SerfsTer21	frameshift_variant	Exon 10 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1311_1312delAG	p.Val438SerfsTer21	frameshift_variant	Exon 10 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1404_1405delAG	p.Val469SerfsTer21	frameshift_variant	Exon 10 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1059_1060delAG	p.Val354SerfsTer21	frameshift_variant	Exon 11 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.870_871delAG	p.Val291SerfsTer21	frameshift_variant	Exon 10 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.846_847delAG	p.Val283fs	frameshift_variant	Exon 9 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.846_847delAG	p.Val283fs	frameshift_variant	Exon 9 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*851_*852delAG		non_coding_transcript_exon_variant	Exon 11 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.846_847delAG		non_coding_transcript_exon_variant	Exon 9 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*613_*614delAG		non_coding_transcript_exon_variant	Exon 12 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*613_*614delAG		non_coding_transcript_exon_variant	Exon 12 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*320_*321delAG		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*613_*614delAG		non_coding_transcript_exon_variant	Exon 10 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.846_847delAG		non_coding_transcript_exon_variant	Exon 9 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*353_*354delAG		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.846_847delAG		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.846_847delAG		non_coding_transcript_exon_variant	Exon 9 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*851_*852delAG		3_prime_UTR_variant	Exon 11 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*613_*614delAG		3_prime_UTR_variant	Exon 12 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*613_*614delAG		3_prime_UTR_variant	Exon 12 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*320_*321delAG		3_prime_UTR_variant	Exon 8 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*613_*614delAG		3_prime_UTR_variant	Exon 10 of 20			ENSP00000505898.1
CUL4B	ENST00000681333.1	n.*353_*354delAG		3_prime_UTR_variant	Exon 10 of 17			ENSP00000505739.1

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

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Jun 19, 2017

Center of Genomic medicine, Geneva, University Hospital of Geneva

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This hemizygous variant in the CUL4B gene was identified in a young patient with developmental disorder. -

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: rs1556206910; hg19: chrX-119675494;