rs869320682

Positions:

chrX-120560544-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The ENST00000371322.11(CUL4B):c.95C>T(p.Pro32Leu) variant causes a missense 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P32T) has been classified as Uncertain significance.

Frequency

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

Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

CUL4B
ENST00000371322.11 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 9.60

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), CUL4B. . Gene score misZ 3.7714 (greater than the threshold 3.09). GenCC has associacion of gene with X-linked intellectual disability, Cabezas type.

BP4

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CUL4B	NM_001079872.2 linkuse as main transcript	c.95C>T	p.Pro32Leu	missense_variant	1/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4 linkuse as main transcript	c.149C>T	p.Pro50Leu	missense_variant	3/22		NP_003579.3
CUL4B	NM_001330624.2 linkuse as main transcript	c.110C>T	p.Pro37Leu	missense_variant	2/21		NP_001317553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11 linkuse as main transcript	c.95C>T	p.Pro32Leu	missense_variant	1/20	1	NM_001079872.2	ENSP00000360373		Q13620-1

Frequencies

GnomAD3 genomes

AF:

0.00000898

AC:

AN:

111400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33576

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

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:

0.00

Gnomad4 OTH exome

AF:

0.0000217

GnomAD4 genome

AF:

0.00000898

AC:

AN:

111400

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

33576

show subpopulations

Gnomad4 AFR

AF:

0.0000327

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Uncertain:1Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

X-linked intellectual disability Cabezas type

Pathogenic:1Benign:1

Likely benign, no assertion criteria provided	clinical testing	Service de Génétique Moléculaire, Hôpital Robert Debré	Oct 02, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -

CUL4B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 31, 2023

The CUL4B c.149C>T variant is predicted to result in the amino acid substitution p.Pro50Leu. This variant was reported in two male siblings with cerebral malformations (Family 10, Vulto-van Silfhout et al. 2015. PubMed ID: 25385192). Functional studies showed that this variant does not alter protein stability or subcellular localization (Vulto-van Silfhout et al. 2015. PubMed ID: 25385192); however, a recent study suggested that this variant may alter mitotic-specific phosphorylation and impact protein-protein interaction (https://www.biorxiv.org/content/10.1101/2022.10.14.512051v1.full.pdf). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. Although we suspect that this variant may be pathogenic, 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

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.099

.;.;T

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.77

T;T;T

M_CAP

Uncertain

0.095

MetaRNN

Benign

0.32

T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.55

.;.;N

MutationTaster

Benign

0.87

N;N;N

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-0.54

N;N;N

REVEL

Benign

0.16

Sift

Uncertain

0.0050

D;D;D

Sift4G

Benign

0.22

T;T;T

Polyphen

0.072

B;.;B

Vest4

0.45

MVP

0.74

MPC

0.66

ClinPred

0.67

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.19

gMVP

0.17

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

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