rs1556220623

Positions:

• chrX-120547191-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001079872.2(CUL4B):​c.721C>T​(p.Gln241Ter) variant causes a stop gained change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 10.0

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 18 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-120547191-G-A is Pathogenic according to our data. Variant chrX-120547191-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 520903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.721C>T	p.Gln241Ter	stop_gained	3/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.775C>T	p.Gln259Ter	stop_gained	5/22		NP_003579.3
CUL4B	NM_001330624.2	c.736C>T	p.Gln246Ter	stop_gained	4/21		NP_001317553.1
CUL4B	NM_001369145.1	c.187C>T	p.Gln63Ter	stop_gained	3/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.721C>T	p.Gln241Ter	stop_gained	3/20	1	NM_001079872.2	ENSP00000360373

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2022

This variant has not been reported in the literature in individuals affected with CUL4B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln259*) in the CUL4B gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in CUL4B are known to be pathogenic (PMID: 17236139, 25385192). ClinVar contains an entry for this variant (Variation ID: 520903). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.66
CADD	Pathogenic	38
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.99	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.95
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: 48

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1556220623; hg19: chrX-119681046;