X-120543779-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PM5PP3_ModerateBS2

The NM_001079872.2(CUL4B):c.1204C>T(p.Arg402Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000644 in 1,086,969 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 2 hemizygotes in GnomAD. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402G) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0000064 ( 0 hom. 2 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.88

Publications

0 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

CUL4B links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chrX-120543779-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 520600.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.933

BS2

High Hemizygotes in GnomAdExome4 at 2 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079872.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL4B	NM_001079872.2	MANE Select	c.1204C>T	p.Arg402Cys	missense	Exon 8 of 20	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4		c.1258C>T	p.Arg420Cys	missense	Exon 10 of 22	NP_003579.3
CUL4B	NM_001330624.2		c.1219C>T	p.Arg407Cys	missense	Exon 9 of 21	NP_001317553.1	K4DI93

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.1204C>T	p.Arg402Cys	missense	Exon 8 of 20	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1		c.1318C>T	p.Arg440Cys	missense	Exon 11 of 23	ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1		c.1258C>T	p.Arg420Cys	missense	Exon 10 of 22	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000644

AC:

AN:

1086969

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

353195

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26208

American (AMR)

AF:

0.00

AC:

AN:

35186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19309

East Asian (EAS)

AF:

0.00

AC:

AN:

30130

South Asian (SAS)

AF:

0.00

AC:

AN:

53885

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40406

Middle Eastern (MID)

AF:

0.000245

AC:

AN:

4089

European-Non Finnish (NFE)

AF:

0.00000721

AC:

AN:

832041

Other (OTH)

AF:

0.00

AC:

AN:

45715

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.90

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.58

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.24

MutationAssessor

Benign

1.6

PhyloP100

9.9

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.83

Sift

Benign

0.032

Sift4G

Uncertain

0.0020

Polyphen

1.0

Vest4

0.71

MutPred

0.73

Gain of methylation at K419 (P = 0.0145)

MVP

0.99

MPC

1.9

ClinPred

1.0

GERP RS

6.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.92

gMVP

0.95

Mutation Taster

=30/70

disease causing

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over