rs1085307760

Variant names:

• chrX-120544606-TTATAA-T
• rs1085307760
• NM_001079872.2:c.953_957delTTATA

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_957delTTATA​(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 (★★). 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:7
• 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]

LOC124905273 (HGNC:):

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 rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.953_957delTTATA	p.Ile318LysfsTer2	frameshift_variant	Exon 6 of 20	ENST00000371322.11	NP_001073341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.953_957delTTATA	p.Ile318LysfsTer2	frameshift_variant	Exon 6 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1067_1071delTTATA	p.Ile356LysfsTer2	frameshift_variant	Exon 9 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1007_1011delTTATA	p.Ile336LysfsTer2	frameshift_variant	Exon 8 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1007_1011delTTATA	p.Ile336LysfsTer2	frameshift_variant	Exon 9 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1007_1011delTTATA	p.Ile336LysfsTer2	frameshift_variant	Exon 11 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.968_972delTTATA	p.Ile323LysfsTer2	frameshift_variant	Exon 7 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.953_957delTTATA	p.Ile318LysfsTer2	frameshift_variant	Exon 6 of 20			ENSP00000501019.6
CUL4B	ENST00000404115.8	c.953_957delTTATA	p.Ile318LysfsTer2	frameshift_variant	Exon 6 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.608_612delTTATA	p.Ile203LysfsTer2	frameshift_variant	Exon 7 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.419_423delTTATA	p.Ile140LysfsTer2	frameshift_variant	Exon 6 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.395_399delTTATA	p.Ile132fs	frameshift_variant	Exon 5 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.395_399delTTATA	p.Ile132fs	frameshift_variant	Exon 5 of 18			ENSP00000505239.1
CUL4B	ENST00000681090.1	c.921-61_921-57delTTATA		intron_variant	Intron 5 of 19			ENSP00000506288.1
CUL4B	ENST00000673919.1	n.*400_*404delTTATA		non_coding_transcript_exon_variant	Exon 7 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.395_399delTTATA		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*162_*166delTTATA		non_coding_transcript_exon_variant	Exon 8 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*162_*166delTTATA		non_coding_transcript_exon_variant	Exon 8 of 22			ENSP00000505343.1
CUL4B	ENST00000681080.1	n.*162_*166delTTATA		non_coding_transcript_exon_variant	Exon 6 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.395_399delTTATA		non_coding_transcript_exon_variant	Exon 5 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.953_957delTTATA		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.395_399delTTATA		non_coding_transcript_exon_variant	Exon 5 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.395_399delTTATA		non_coding_transcript_exon_variant	Exon 5 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*400_*404delTTATA		3_prime_UTR_variant	Exon 7 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*162_*166delTTATA		3_prime_UTR_variant	Exon 8 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*162_*166delTTATA		3_prime_UTR_variant	Exon 8 of 22			ENSP00000505343.1
CUL4B	ENST00000681080.1	n.*162_*166delTTATA		3_prime_UTR_variant	Exon 6 of 20			ENSP00000505898.1
CUL4B	ENST00000680918.1	n.363-408_363-404delTTATA		intron_variant	Intron 4 of 17			ENSP00000505955.1

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:6

May 13, 2021

Pediatric Genetics Clinic, Sheba Medical Center

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Developmental and Behavioral Pediatrics, First Affiliated Hospital of Jilin University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 01, 2022

3billion

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Nov 20, 2023

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Criteria applied: PVS1,PS2,PS4_MOD,PM2_SUP -

-

Juno Genomics, Hangzhou Juno Genomics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PM2_Supporting+PVS1+PS4_Supporting+PP1 -

Apr 01, 2017

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Mar 17, 2025

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Frameshift variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 33057194, 19377476, 20064923, 25385192, 17236139, 31069529, 38113761, 38331954, 39984621) -

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;