rs1556200443

Variant names:

• chrX-120538658-AC-A
• rs1556200443
• NM_001079872.2:c.1852+1delG

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_001079872.2(CUL4B):​c.1852+1delG variant causes a splice donor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 splice_donor, intron
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• 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 Likely_pathogenic. Variant got 6 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. Cryptic splice site detected, with MaxEntScore 4.9, offset of 0 (no position change), new splice context is: catGTaggt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120538658-AC-A is Pathogenic according to our data. Variant chrX-120538658-AC-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 521673.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.1852+1delG		splice_donor_variant, intron_variant	Intron 13 of 19	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1906+1delG		splice_donor_variant, intron_variant	Intron 15 of 21		NP_003579.3
CUL4B	NM_001330624.2	c.1867+1delG		splice_donor_variant, intron_variant	Intron 14 of 20		NP_001317553.1
CUL4B	NM_001369145.1	c.1318+1delG		splice_donor_variant, intron_variant	Intron 13 of 19		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1852+1delG		splice_donor_variant, intron_variant	Intron 13 of 19	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1966+1delG		splice_donor_variant, intron_variant	Intron 16 of 22			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1906+1delG		splice_donor_variant, intron_variant	Intron 15 of 21			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1906+1delG		splice_donor_variant, intron_variant	Intron 16 of 22			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1906+1delG		splice_donor_variant, intron_variant	Intron 18 of 24			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1867+1delG		splice_donor_variant, intron_variant	Intron 14 of 20	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1852+1delG		splice_donor_variant, intron_variant	Intron 13 of 19			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1759+1delG		splice_donor_variant, intron_variant	Intron 13 of 19			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1852+1delG		splice_donor_variant, intron_variant	Intron 13 of 18	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1507+1delG		splice_donor_variant, intron_variant	Intron 14 of 20			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1318+1delG		splice_donor_variant, intron_variant	Intron 13 of 19	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1294+1delG		splice_donor_variant, intron_variant	Intron 12 of 19			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1189+1delG		splice_donor_variant, intron_variant	Intron 11 of 17			ENSP00000505239.1
CUL4B	ENST00000681333.1	n.*2296delG		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000681333.1	n.*2296delG		3_prime_UTR_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000673919.1	n.*1299+1delG		splice_donor_variant, intron_variant	Intron 14 of 20			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1294+1delG		splice_donor_variant, intron_variant	Intron 12 of 17			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1061+1delG		splice_donor_variant, intron_variant	Intron 15 of 21			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1061+1delG		splice_donor_variant, intron_variant	Intron 15 of 21			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*768+1delG		splice_donor_variant, intron_variant	Intron 11 of 17			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1061+1delG		splice_donor_variant, intron_variant	Intron 13 of 19			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.1294+1delG		splice_donor_variant, intron_variant	Intron 12 of 19			ENSP00000505973.1
CUL4B	ENST00000681869.1	n.1294+1delG		splice_donor_variant, intron_variant	Intron 12 of 16			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.1294+1delG		splice_donor_variant, intron_variant	Intron 12 of 19			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 20

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Apr 24, 2017

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_DG_spliceai		1.0		Position offset: 3
DS_DL_spliceai		1.0		Position offset: 2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1556200443; hg19: chrX-119672513;