NM_001079872.2:c.1852+1G>T

Variant names:

• chrX-120538659-C-A
• rs797044862
• NM_001079872.2:c.1852+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PS3 PM2 PP5_Moderate

The NM_001079872.2(CUL4B):​c.1852+1G>T variant causes a splice donor, intron 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 (★). ClinVar reports functional evidence for this variant: "SCV002034868: 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).".

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

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]

CUL4B Gene-Disease associations (from GenCC):

• X-linked intellectual disability, Cabezas type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.04129464 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV002034868: 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).
• 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 VariationId is 208796.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079872.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.1852+1G>T		splice_donor intron	N/A	NP_001073341.1	Q13620-1
	CUL4B	NM_003588.4		c.1906+1G>T		splice_donor intron	N/A	NP_003579.3
	CUL4B	NM_001330624.2		c.1867+1G>T		splice_donor intron	N/A	NP_001317553.1	K4DI93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.1852+1G>T		splice_donor intron	N/A	ENSP00000360373.5	Q13620-1
	CUL4B	ENST00000681206.1		c.1966+1G>T		splice_donor intron	N/A	ENSP00000505480.1	A0A7P0T954
	CUL4B	ENST00000680673.1		c.1906+1G>T		splice_donor intron	N/A	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 23

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	CUL4B-related X-linked intellectual disability (1)
1	-	-	X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		7.9
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs797044862; hg19: chrX-119672514;