X-120530105-TACTGGAAATTTCA-T

Variant names:

• chrX-120530105-TACTGGAAATTTCA-T
• NM_001079872.2:c.2576_2588delTGAAATTTCCAGT

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PP5_Moderate

The NM_001079872.2(CUL4B):​c.2576_2588delTGAAATTTCCAGT​(p.Leu859fs) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CUL4B NM_001079872.2 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.60
• Publications: 0 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PP5: Variant X-120530105-TACTGGAAATTTCA-T is Pathogenic according to our data. Variant chrX-120530105-TACTGGAAATTTCA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2506462.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2576_2588delTGAAATTTCCAGT	p.Leu859fs	frameshift_variant	Exon 19 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2630_2642delTGAAATTTCCAGT	p.Leu877fs	frameshift_variant	Exon 21 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.2591_2603delTGAAATTTCCAGT	p.Leu864fs	frameshift_variant	Exon 20 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.2042_2054delTGAAATTTCCAGT	p.Leu681fs	frameshift_variant	Exon 19 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2576_2588delTGAAATTTCCAGT	p.Leu859fs	frameshift_variant	Exon 19 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2690_2702delTGAAATTTCCAGT	p.Leu897fs	frameshift_variant	Exon 22 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2630_2642delTGAAATTTCCAGT	p.Leu877fs	frameshift_variant	Exon 21 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2630_2642delTGAAATTTCCAGT	p.Leu877fs	frameshift_variant	Exon 22 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2630_2642delTGAAATTTCCAGT	p.Leu877fs	frameshift_variant	Exon 24 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2591_2603delTGAAATTTCCAGT	p.Leu864fs	frameshift_variant	Exon 20 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2582_2594delTGAAATTTCCAGT	p.Leu861fs	frameshift_variant	Exon 19 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2483_2495delTGAAATTTCCAGT	p.Leu828fs	frameshift_variant	Exon 19 of 20			ENSP00000506288.1
CUL4B	ENST00000679927.1	c.2231_2243delTGAAATTTCCAGT	p.Leu744fs	frameshift_variant	Exon 20 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2042_2054delTGAAATTTCCAGT	p.Leu681fs	frameshift_variant	Exon 19 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.2018_2030delTGAAATTTCCAGT	p.Leu673fs	frameshift_variant	Exon 18 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1913_1925delTGAAATTTCCAGT	p.Leu638fs	frameshift_variant	Exon 17 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*2023_*2035delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 20 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*132_*144delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1785_*1797delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 21 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1785_*1797delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 21 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1492_*1504delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 17 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1785_*1797delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*742_*754delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3469_*3481delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 16 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*748_*760delTGAAATTTCCAGT		non_coding_transcript_exon_variant	Exon 19 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2023_*2035delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 20 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*132_*144delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 17 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1785_*1797delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 21 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1785_*1797delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 21 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1492_*1504delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 17 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1785_*1797delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*742_*754delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3469_*3481delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 16 of 17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*748_*760delTGAAATTTCCAGT		3_prime_UTR_variant	Exon 19 of 20			ENSP00000505777.1
CUL4B	ENST00000404115.8	c.2439+2304_2439+2316delTGAAATTTCCAGT		intron_variant	Intron 18 of 18	1		ENSP00000384109.4

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: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Oct 20, 2022

Eurofins-Biomnis

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.6

Splicing

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

Other links and lift over

hg19: chrX-119663960;