rs755306871

Positions:

chrX-120560345-C-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001079872.2(CUL4B):c.294G>T(p.Gln98His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 1,207,901 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 22)

Exomes 𝑓: 0.000014 ( 0 hom. 4 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2B:1

Conservation

PhyloP100: 2.50

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:

CUL4B (HGNC:):

CUL4B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

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=0.17395201).

BS2

High Hemizygotes in GnomAdExome4 at 4 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2 linkuse as main transcript	c.294G>T	p.Gln98His	missense_variant	1/20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 linkuse as main transcript	c.348G>T	p.Gln116His	missense_variant	3/22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 linkuse as main transcript	c.309G>T	p.Gln103His	missense_variant	2/21		NP_001317553.1	K4DI93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CUL4B	ENST00000371322.11 linkuse as main transcript	c.294G>T	p.Gln98His	missense_variant	1/20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 linkuse as main transcript	c.309G>T	p.Gln103His	missense_variant	2/23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 linkuse as main transcript	c.348G>T	p.Gln116His	missense_variant	3/22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 linkuse as main transcript	c.348G>T	p.Gln116His	missense_variant	4/23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 linkuse as main transcript	c.348G>T	p.Gln116His	missense_variant	6/25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 linkuse as main transcript	c.309G>T	p.Gln103His	missense_variant	2/21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 linkuse as main transcript	c.294G>T	p.Gln98His	missense_variant	1/20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 linkuse as main transcript	c.294G>T	p.Gln98His	missense_variant	1/20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 linkuse as main transcript	c.294G>T	p.Gln98His	missense_variant	1/19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000679927.1 linkuse as main transcript	c.-52G>T		5_prime_UTR_variant	2/21			ENSP00000505603.1	A0A7P0T9L3
CUL4B	ENST00000673919.1 linkuse as main transcript	n.294G>T		non_coding_transcript_exon_variant	1/21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679432.1 linkuse as main transcript	n.279G>T		non_coding_transcript_exon_variant	1/22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000681333.1 linkuse as main transcript	n.294G>T		non_coding_transcript_exon_variant	1/17			ENSP00000505739.1	A0A7P0T9R8

Frequencies

GnomAD3 genomes

AF:

0.00000894

AC:

AN:

111846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34004

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000275

AC:

AN:

181684

Hom.:

AF XY:

0.0000151

AC XY:

AN XY:

66220

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000147

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000137

AC:

AN:

1096055

Hom.:

Cov.:

AF XY:

0.0000111

AC XY:

AN XY:

361637

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000142

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:

0.0000119

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000894

AC:

AN:

111846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34004

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000188

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000227

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked intellectual disability Cabezas type

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Daryl Scott Lab, Baylor College of Medicine	Nov 10, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 06, 2020	This sequence change replaces glutamine with histidine at codon 116 of the CUL4B protein (p.Gln116His). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and histidine. This variant is present as hemizygous in an individual in the population databases (rs755306871, ExAC 0.01%) but has not been reported in the literature in individuals with a CUL4B-related disease. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -

Intellectual disability

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Jan 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.26

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.087

.;.;T

FATHMM_MKL

Uncertain

0.77

LIST_S2

Benign

0.85

D;T;T

M_CAP

Benign

0.029

MetaRNN

Benign

0.17

T;T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.81

.;.;L

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-0.38

N;N;N

REVEL

Benign

0.20

Sift

Uncertain

0.0040

D;D;D

Sift4G

Benign

0.077

T;T;T

Polyphen

0.0010

B;.;B

Vest4

0.28

MutPred

0.20

.;.;Gain of relative solvent accessibility (P = 0.0522);

MVP

0.93

MPC

0.60

ClinPred

0.13

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.50

gMVP

0.83

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