rs797044862

chrX-120538659-C-AchrX-120538659-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1_Moderate PM2 PP3_Strong 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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Splicing variant, 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
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• 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	UniProt
CUL4B	NM_001079872.2	c.1852+1G>T		splice_donor_variant		ENST00000371322.11
CUL4B	NM_001330624.2	c.1867+1G>T		splice_donor_variant
CUL4B	NM_001369145.1	c.1318+1G>T		splice_donor_variant
CUL4B	NM_003588.4	c.1906+1G>T		splice_donor_variant

Ensembl

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

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;