X-120530099-T-A

Variant names:

• chrX-120530099-T-A
• NM_001079872.2:c.2592+3A>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001079872.2(CUL4B):​c.2592+3A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000913 in 1,095,077 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: CUL4B NM_001079872.2 splice_region, intron
• Scores: Splicing: ADA: 0.8508
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.153

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2592+3A>T		splice_region_variant, intron_variant	Intron 19 of 19	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2646+3A>T		splice_region_variant, intron_variant	Intron 21 of 21		NP_003579.3
CUL4B	NM_001330624.2	c.2607+3A>T		splice_region_variant, intron_variant	Intron 20 of 20		NP_001317553.1
CUL4B	NM_001369145.1	c.2058+3A>T		splice_region_variant, intron_variant	Intron 19 of 19		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2592+3A>T		splice_region_variant, intron_variant	Intron 19 of 19	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2706+3A>T		splice_region_variant, intron_variant	Intron 22 of 22			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2646+3A>T		splice_region_variant, intron_variant	Intron 21 of 21			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2646+3A>T		splice_region_variant, intron_variant	Intron 22 of 22			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2646+3A>T		splice_region_variant, intron_variant	Intron 24 of 24			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2607+3A>T		splice_region_variant, intron_variant	Intron 20 of 20	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2598+3A>T		splice_region_variant, intron_variant	Intron 19 of 19			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2499+3A>T		splice_region_variant, intron_variant	Intron 19 of 19			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2439+2323A>T		intron_variant	Intron 18 of 18	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2247+3A>T		splice_region_variant, intron_variant	Intron 20 of 20			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2058+3A>T		splice_region_variant, intron_variant	Intron 19 of 19	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.2034+3A>T		splice_region_variant, intron_variant	Intron 18 of 19			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1929+3A>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*2039+3A>T		splice_region_variant, intron_variant	Intron 20 of 20			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*148+3A>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1801+3A>T		splice_region_variant, intron_variant	Intron 21 of 21			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1801+3A>T		splice_region_variant, intron_variant	Intron 21 of 21			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1508+3A>T		splice_region_variant, intron_variant	Intron 17 of 17			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1801+3A>T		splice_region_variant, intron_variant	Intron 19 of 19			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*758+3A>T		splice_region_variant, intron_variant	Intron 19 of 19			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3485+3A>T		splice_region_variant, intron_variant	Intron 16 of 16			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*764+3A>T		splice_region_variant, intron_variant	Intron 19 of 19			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.13e-7 AC: 1 AN: 1095077 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 360779

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: 0.00000119

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Uncertain:1

Sep 09, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant has not been reported in the literature in individuals affected with CUL4B-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 21 of the CUL4B gene. It does not directly change the encoded amino acid sequence of the CUL4B protein. It affects a nucleotide within the consensus splice site. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	17
DANN	Benign	0.89

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.85
dbscSNV1_RF	Benign	0.53
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119663954;