X-120545519-T-C

Position:

• chrX-120545519-T-C

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001079872.2(CUL4B):​c.847-2A>G variant causes a splice acceptor, 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 (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CUL4B NM_001079872.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99

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 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of 35, new splice context is: atttttttgtttctggatAGaac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120545519-T-C is Pathogenic according to our data. Variant chrX-120545519-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 11340.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.847-2A>G		splice_acceptor_variant, intron_variant		ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.901-2A>G		splice_acceptor_variant, intron_variant			NP_003579.3
CUL4B	NM_001330624.2	c.862-2A>G		splice_acceptor_variant, intron_variant			NP_001317553.1
CUL4B	NM_001369145.1	c.313-2A>G		splice_acceptor_variant, intron_variant			NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.847-2A>G		splice_acceptor_variant, intron_variant		1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.961-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505480.1
CUL4B	ENST00000680673.1	c.901-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505084.1
CUL4B	ENST00000681253.1	c.901-2A>G		splice_acceptor_variant, intron_variant				ENSP00000506259.1
CUL4B	ENST00000681652.1	c.901-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505176.1
CUL4B	ENST00000336592.11	c.862-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.847-2A>G		splice_acceptor_variant, intron_variant				ENSP00000501019.6
CUL4B	ENST00000681090.1	c.847-2A>G		splice_acceptor_variant, intron_variant				ENSP00000506288.1
CUL4B	ENST00000404115.8	c.847-2A>G		splice_acceptor_variant, intron_variant		1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.502-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505603.1
CUL4B	ENST00000371323.3	c.313-2A>G		splice_acceptor_variant, intron_variant		5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505562.1
CUL4B	ENST00000679844.1	c.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*294-2A>G		splice_acceptor_variant, intron_variant				ENSP00000500994.1
CUL4B	ENST00000674073.2	n.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*56-2A>G		splice_acceptor_variant, intron_variant				ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*56-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505343.1
CUL4B	ENST00000680918.1	n.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*56-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505898.1
CUL4B	ENST00000681189.1	n.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505973.1
CUL4B	ENST00000681333.1	n.847-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505739.1
CUL4B	ENST00000681869.1	n.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505597.1
CUL4B	ENST00000681908.1	n.289-2A>G		splice_acceptor_variant, intron_variant				ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1037234 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 320716

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		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: rs786200913; hg19: chrX-119679374;