rs754330779

Positions:

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP3PP5BP3BS2

The NM_001079872.2(CUL4B):c.369_377del(p.Ser126_Ser128del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000063 ( 0 hom., 1 hem., cov: 22)

Exomes 𝑓: 0.000043 ( 0 hom. 15 hem. )

Consequence

CUL4B
NM_001079872.2 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1U:2

Conservation

PhyloP100: 9.26

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PP3

No computational evidence supports a deleterious effect, but strongly conserved according to phyloP

PP5

Variant X-120560261-TGAGGAGGAG-T is Pathogenic according to our data. Variant chrX-120560261-TGAGGAGGAG-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 504176.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.

BP3

Nonframeshift variant in repetitive region in NM_001079872.2

BS2

High Hemizygotes in GnomAdExome4 at 15 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CUL4B	NM_001079872.2 linkuse as main transcript	c.369_377del	p.Ser126_Ser128del	inframe_deletion	1/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_001330624.2 linkuse as main transcript	c.384_392del	p.Ser131_Ser133del	inframe_deletion	2/21		NP_001317553.1
CUL4B	NM_003588.4 linkuse as main transcript	c.423_431del	p.Ser144_Ser146del	inframe_deletion	3/22		NP_003579.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11 linkuse as main transcript	c.369_377del	p.Ser126_Ser128del	inframe_deletion	1/20	1	NM_001079872.2	ENSP00000360373		Q13620-1

Frequencies

GnomAD3 genomes

AF:

0.0000631

AC:

AN:

111015

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33341

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000958

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000113

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000231

AC:

AN:

173145

Hom.:

AF XY:

0.00

AC XY:

AN XY:

61627

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000514

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000428

AC:

AN:

1097200

Hom.:

AF XY:

0.0000413

AC XY:

AN XY:

362924

show subpopulations

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:

0.0000559

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000631

AC:

AN:

111015

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33341

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000958

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000113

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 31, 2018

The c.423_431delCTCCTCCTC variant in the XXX gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The c.423_431delCTCCTCCTC variant causes an inframe deletion of three amino acids starting at Serine 144, denoted p.S144_S146del. The c.423_431delCTCCTCCTC variant is observed in 5/86720 (0.0058%) alleles from individuals of non-Finnish European background, and 5/190079 total alleles in large population cohorts (Lek et al., 2016). We interpret c.423_431delCTCCTCCTC as a likely pathogenic variant. -

X-linked intellectual disability Cabezas type

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2019

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. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. This variant has not been reported in the literature in individuals with CUL4B-related conditions. ClinVar contains an entry for this variant (Variation ID:¬†504176). This variant is present in population databases (rs756411375, ExAC 0.004%), including at least one homozygous and/or hemizygous individual. This variant, c.423_431del, results in the deletion of 3 amino acid(s) of the CUL4B protein (p.Ser144_Ser146del), but otherwise preserves the integrity of the reading frame. -

CUL4B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 31, 2024

The CUL4B c.423_431del9 variant is predicted to result in an in-frame deletion (p.Ser144_Ser146del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0057% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over