rs1085307760

Positions:

• chrX-120544606-TTATAA-T

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.953_957del​(p.Ile318LysfsTer2) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. I318I) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CUL4B NM_001079872.2 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.25

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-120544606-TTATAA-T is Pathogenic according to our data. Variant chrX-120544606-TTATAA-T is described in ClinVar as [Pathogenic]. Clinvar id is 426723.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120544606-TTATAA-T is described in Lovd as [Pathogenic]. Variant chrX-120544606-TTATAA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL4B	NM_001079872.2	c.953_957del	p.Ile318LysfsTer2	frameshift_variant	6/20	ENST00000371322.11
CUL4B	NM_001330624.2	c.968_972del	p.Ile323LysfsTer2	frameshift_variant	7/21
CUL4B	NM_001369145.1	c.419_423del	p.Ile140LysfsTer2	frameshift_variant	6/20
CUL4B	NM_003588.4	c.1007_1011del	p.Ile336LysfsTer2	frameshift_variant	8/22

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL4B	ENST00000371322.11	c.953_957del	p.Ile318LysfsTer2	frameshift_variant	6/20	1	NM_001079872.2

Frequencies

GnomAD3 genomes Cov.: 22

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:5

Pathogenic, no assertion criteria provided	clinical testing	Pediatric Genetics Clinic, Sheba Medical Center	May 13, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	Apr 01, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Sep 01, 2022	The variant is not observed in the gnomAD v2.1.1 dataset. Frameshift variant is predicted to result in a loss or disruption of normal protein function through nonsense-mediated decay (NMD) or protein truncation. Multiple pathogenic variants are reported downstream of the variant. The variant has been reported at least twice as pathogenic without evidence for the classification (ClinVar ID: VCV000426723 / PMID: 17236139). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Nov 20, 2023	Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Apr 06, 2017

The c.1007_1011delTTATA variant in the CUL4B gene has been reported previously in families with X-linked intellectual disability (Tarpey et al., 2007; Vulto-van Silfhout et al., 2015). The c.1007_1011delTTATA variant causes a frameshift starting with codon Isoleucine 336, changes this amino acid to a Lysine residue, and creates a premature Stop codon at position 2 of the new reading frame, denoted p.Ile336LysfsX2. Functional studies on patient-derived cells demonstrate that this variant significantly reduces CUL4B gene expression (Kerzendorfer et al., 2010). The c.1007_1011delTTATA variant is not observed in large population cohorts (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). We interpret c.1007_1011delTTATA as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1085307760; hg19: chrX-119678461;