rs797044862

Positions:

• chrX-120538659-C-A
• chrX-120538659-C-T

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.1852+1G>T variant causes a splice donor 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. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.88

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: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04092262 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120538659-C-A is Pathogenic according to our data. Variant chrX-120538659-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 208796.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-120538659-C-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1852+1G>T		splice_donor_variant		ENST00000371322.11	NP_001073341.1
CUL4B	NM_001330624.2	c.1867+1G>T		splice_donor_variant			NP_001317553.1
CUL4B	NM_001369145.1	c.1318+1G>T		splice_donor_variant			NP_001356074.1
CUL4B	NM_003588.4	c.1906+1G>T		splice_donor_variant			NP_003579.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1852+1G>T		splice_donor_variant		1	NM_001079872.2	ENSP00000360373

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jan 01, 2015

- -

CUL4B-related X-linked intellectual disability Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Sep 13, 2021

The CUL4B c.1906+1G>T variant occurs in a canonical splice site (donor) and is therefore predicted to disrupt the normal gene product. This variant has been reported in a hemizygous state in two brothers affected with intellectual disability; the mother and two similarly affected maternal half-brothers were not tested (Vulto-van Silfhout et al. 2015). In addition, an alternative nucleotide change at the same position, c.1906+1G>A, has been reported in a de novo hemizygous state in an individual with X-linked syndromic intellectual disability of Cabezas type (Rossi et al. 2017). The c.1906+1G>T variant is not found in version 2.1.1 or version 3.1.1 of the Genome Aggregation Database despite its location in a region of good sequencing coverage, which suggests that the variant is rare. RT-PCR analysis showed the c.1906+1G>T variant abolished the splice donor site of exon 15, resulting in exon 15 skipping and deletion of 37 amino acid residues within the cullin domain (Vulto-van Silfhout et al. 2015). Based on the available evidence, the c.1906+1G>T variant is classified as pathogenic for CUL4B-related X-linked intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	35
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	0.98	D
MutationTaster	Benign	1.0	D;D;D
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.77		Position offset: 2
DS_DL_spliceai		1.0		Position offset: 1

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044862; hg19: chrX-119672514;