rs754330779

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3PP5BP3BS2

The NM_001079872.2(CUL4B):c.369_377delCTCCTCCTC(p.Ser124_Ser126del) variant causes a disruptive 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 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

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

Conservation

PhyloP100: 9.26

Publications

1 publications found

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 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

CUL4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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: {Uncertain_significance=1, Likely_pathogenic=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 rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2 link	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 link	c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 3 of 22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 link	c.384_392delCTCCTCCTC	p.Ser129_Ser131del	disruptive_inframe_deletion	Exon 2 of 21		NP_001317553.1	K4DI93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL4B	ENST00000371322.11 link	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 link	c.384_392delCTCCTCCTC	p.Ser129_Ser131del	disruptive_inframe_deletion	Exon 2 of 23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 link	c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 3 of 22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 link	c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 4 of 23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 link	c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 6 of 25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 link	c.384_392delCTCCTCCTC	p.Ser129_Ser131del	disruptive_inframe_deletion	Exon 2 of 21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 link	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 link	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 link	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000679927.1 link	c.24_32delCTCCTCCTC	p.Ser9_Ser11del	disruptive_inframe_deletion	Exon 2 of 21			ENSP00000505603.1	A0A7P0T9L3
CUL4B	ENST00000673919.1 link	n.369_377delCTCCTCCTC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679432.1 link	n.354_362delCTCCTCCTC		non_coding_transcript_exon_variant	Exon 1 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000681333.1 link	n.369_377delCTCCTCCTC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000505739.1	A0A7P0T9R8

Frequencies

GnomAD3 genomes

AF:

0.0000631

AC:

AN:

111015

Hom.:

Cov.:

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

GnomAD2 exomes

AF:

0.0000231

AC:

AN:

173145

AF XY:

0.00

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 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

African (AFR)

AF:

0.00

AC:

AN:

26382

American (AMR)

AF:

0.00

AC:

AN:

35197

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19372

East Asian (EAS)

AF:

0.00

AC:

AN:

30195

South Asian (SAS)

AF:

0.00

AC:

AN:

54099

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40449

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4133

European-Non Finnish (NFE)

AF:

0.0000559

AC:

AN:

841308

Other (OTH)

AF:

0.00

AC:

AN:

46065

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.434

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000631

AC:

AN:

111015

Hom.:

Cov.:

AF XY:

0.0000300

AC XY:

AN XY:

33341

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30539

American (AMR)

AF:

0.0000958

AC:

AN:

10437

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2637

East Asian (EAS)

AF:

0.00

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2654

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5898

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.000113

AC:

AN:

52899

Other (OTH)

AF:

0.00

AC:

AN:

1493

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Jan 31, 2018

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 26, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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, 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. This variant is present in population databases (rs756411375, ExAC 0.004%), including at least one homozygous and/or hemizygous individual. 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). Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the affected amino acid(s) is currently unknown. -

CUL4B-related disorder

Uncertain:1

Jan 31, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

PhyloP100

9.3

Splicing

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

Publications

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rs754330779

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over