rs760294805

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP6BS1BS2

The NM_001079872.2(CUL4B):c.319C>G(p.Leu107Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,209,508 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 100 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000098 ( 0 hom., 3 hem., cov: 22)

Exomes 𝑓: 0.00023 ( 0 hom. 97 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 1.91

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08543086).

BP6

Variant X-120560320-G-C is Benign according to our data. Variant chrX-120560320-G-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 533698.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000233 (256/1097625) while in subpopulation NFE AF = 0.000291 (245/841714). AF 95% confidence interval is 0.000261. There are 0 homozygotes in GnomAdExome4. There are 97 alleles in the male GnomAdExome4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Hemizygotes in GnomAd4 at 3 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2 link	c.319C>G	p.Leu107Val	missense_variant	Exon 1 of 20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 link	c.373C>G	p.Leu125Val	missense_variant	Exon 3 of 22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 link	c.334C>G	p.Leu112Val	missense_variant	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.319C>G	p.Leu107Val	missense_variant	Exon 1 of 20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 link	c.334C>G	p.Leu112Val	missense_variant	Exon 2 of 23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 link	c.373C>G	p.Leu125Val	missense_variant	Exon 3 of 22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 link	c.373C>G	p.Leu125Val	missense_variant	Exon 4 of 23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 link	c.373C>G	p.Leu125Val	missense_variant	Exon 6 of 25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 link	c.334C>G	p.Leu112Val	missense_variant	Exon 2 of 21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 link	c.319C>G	p.Leu107Val	missense_variant	Exon 1 of 20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 link	c.319C>G	p.Leu107Val	missense_variant	Exon 1 of 20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 link	c.319C>G	p.Leu107Val	missense_variant	Exon 1 of 19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000673919.1 link	n.319C>G		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679432.1 link	n.304C>G		non_coding_transcript_exon_variant	Exon 1 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000681333.1 link	n.319C>G		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000505739.1	A0A7P0T9R8
CUL4B	ENST00000679927.1 link	c.-27C>G		5_prime_UTR_variant	Exon 2 of 21			ENSP00000505603.1	A0A7P0T9L3

Frequencies

GnomAD3 genomes

AF:

0.0000983

AC:

AN:

111883

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000976

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.000150

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000437

AC:

AN:

182857

AF XY:

0.0000445

show subpopulations

Gnomad AFR exome

AF:

0.000152

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:

0.0000735

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000233

AC:

256

AN:

1097625

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

AN XY:

363019

show subpopulations

African (AFR)

AF:

0.000114

AC:

AN:

26381

American (AMR)

AF:

0.00

AC:

AN:

35169

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19347

East Asian (EAS)

AF:

0.00

AC:

AN:

30200

South Asian (SAS)

AF:

0.00

AC:

AN:

54107

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40504

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4132

European-Non Finnish (NFE)

AF:

0.000291

AC:

245

AN:

841714

Other (OTH)

AF:

0.000174

AC:

AN:

46071

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.470

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000983

AC:

AN:

111883

Hom.:

Cov.:

AF XY:

0.0000881

AC XY:

AN XY:

34061

show subpopulations

African (AFR)

AF:

0.0000976

AC:

AN:

30749

American (AMR)

AF:

0.00

AC:

AN:

10548

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2651

East Asian (EAS)

AF:

0.00

AC:

AN:

3567

South Asian (SAS)

AF:

0.00

AC:

AN:

2679

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6067

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.000150

AC:

AN:

53186

Other (OTH)

AF:

0.00

AC:

AN:

1512

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000102

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.000218

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jan 31, 2018

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.L125V variant (also known as c.373C>G), located in coding exon 2 of the CUL4B gene, results from a C to G substitution at nucleotide position 373. The leucine at codon 125 is replaced by valine, an amino acid with highly similar properties. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

X-linked intellectual disability Cabezas type

Benign:1

Aug 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

CUL4B-related disorder

Benign:1

May 17, 2023

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided

Benign:1

Feb 02, 2023

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

See Variant Classification Assertion Criteria. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.061

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.64

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.077

.;.;T

FATHMM_MKL

Benign

0.56

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.015

MetaRNN

Benign

0.085

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.69

.;.;N

PhyloP100

1.9

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-0.17

N;N;N

REVEL

Benign

0.038

Sift

Benign

0.40

T;T;T

Sift4G

Benign

0.26

T;T;T

Polyphen

0.0

B;.;B

Vest4

0.078

MVP

0.70

MPC

0.64

ClinPred

0.0083

GERP RS

1.9

PromoterAI

-0.015

Neutral

(source)

Varity_R

0.088

gMVP

0.41

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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

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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