rs869320682

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The ENST00000679927.1(CUL4B):c.-251C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000166 in 1,206,671 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CUL4B
ENST00000679927.1 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity no assertion criteria provided P:1U:1B:1

Conservation

PhyloP100: 9.60

Publications

4 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: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.320854).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000679927.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CUL4B	NM_001079872.2	MANE Select	c.95C>T	p.Pro32Leu	missense	Exon 1 of 20	NP_001073341.1
CUL4B	NM_003588.4		c.149C>T	p.Pro50Leu	missense	Exon 3 of 22	NP_003579.3
CUL4B	NM_001330624.2		c.110C>T	p.Pro37Leu	missense	Exon 2 of 21	NP_001317553.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CUL4B	ENST00000679927.1		c.-251C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 21	ENSP00000505603.1
CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.95C>T	p.Pro32Leu	missense	Exon 1 of 20	ENSP00000360373.5
CUL4B	ENST00000681206.1		c.110C>T	p.Pro37Leu	missense	Exon 2 of 23	ENSP00000505480.1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111400

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000327

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

9.13e-7

AC:

AN:

1095271

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

360915

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26360

American (AMR)

AF:

0.00

AC:

AN:

34817

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19343

East Asian (EAS)

AF:

0.00

AC:

AN:

30142

South Asian (SAS)

AF:

0.00

AC:

AN:

53756

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40209

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4035

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

840625

Other (OTH)

AF:

0.0000217

AC:

AN:

45984

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

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:

0.00000898

AC:

AN:

111400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33576

show subpopulations

African (AFR)

AF:

0.0000327

AC:

AN:

30588

American (AMR)

AF:

0.00

AC:

AN:

10478

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3541

South Asian (SAS)

AF:

0.00

AC:

AN:

2679

European-Finnish (FIN)

AF:

0.00

AC:

AN:

5959

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53083

Other (OTH)

AF:

0.00

AC:

AN:

1499

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

X-linked intellectual disability Cabezas type (2)

CUL4B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.32

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.55

PhyloP100

9.6

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.54

REVEL

Benign

0.16

Sift

Uncertain

0.0050

Sift4G

Benign

0.22

Polyphen

0.072

Vest4

0.45

MVP

0.74

MPC

0.66

ClinPred

0.67

GERP RS

5.6

PromoterAI

-0.030

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.17

Mutation Taster

=11/89

disease causing (ClinVar)

(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

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over