rs757649304

Variant names:

Variant summary

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

The NM_001079872.2(CUL4B):c.1309G>A(p.Ala437Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000369 in 1,084,033 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: not found (cov: 22)

Exomes 𝑓: 0.0000037 ( 0 hom. 1 hem. )

Consequence

CUL4B
NM_001079872.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 6.06

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: 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=0.28231257).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 9 of 20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 11 of 22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 link	c.1324G>A	p.Ala442Thr	missense_variant	Exon 10 of 21		NP_001317553.1	K4DI93
CUL4B	NM_001369145.1 link	c.775G>A	p.Ala259Thr	missense_variant	Exon 9 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL4B	ENST00000371322.11 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 9 of 20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 link	c.1423G>A	p.Ala475Thr	missense_variant	Exon 12 of 23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 11 of 22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 12 of 23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 link	c.1363G>A	p.Ala455Thr	missense_variant	Exon 14 of 25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 link	c.1324G>A	p.Ala442Thr	missense_variant	Exon 10 of 21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 9 of 20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 link	c.1216G>A	p.Ala406Thr	missense_variant	Exon 9 of 20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 link	c.1309G>A	p.Ala437Thr	missense_variant	Exon 9 of 19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000679927.1 link	c.964G>A	p.Ala322Thr	missense_variant	Exon 10 of 21			ENSP00000505603.1	A0A7P0T9L3
CUL4B	ENST00000371323.3 link	c.775G>A	p.Ala259Thr	missense_variant	Exon 9 of 20	5		ENSP00000360374.3	Q13620-3
CUL4B	ENST00000680474.1 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 8 of 20			ENSP00000505562.1	A0A7P0T9C8
CUL4B	ENST00000679844.1 link	c.751G>A	p.Ala251Thr	missense_variant	Exon 8 of 18			ENSP00000505239.1	A0A7P0T8P8
CUL4B	ENST00000673919.1 link	n.*756G>A		non_coding_transcript_exon_variant	Exon 10 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000674073.2 link	n.751G>A		non_coding_transcript_exon_variant	Exon 8 of 18			ENSP00000501262.2	A0A669KBG9
CUL4B	ENST00000679405.1 link	n.*518G>A		non_coding_transcript_exon_variant	Exon 11 of 22			ENSP00000504985.1	A0A7P0Z439
CUL4B	ENST00000679432.1 link	n.*518G>A		non_coding_transcript_exon_variant	Exon 11 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000680918.1 link	n.*225G>A		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000505955.1	A0A7P0Z4G9
CUL4B	ENST00000681080.1 link	n.*518G>A		non_coding_transcript_exon_variant	Exon 9 of 20			ENSP00000505898.1	A0A7P0Z4E4
CUL4B	ENST00000681189.1 link	n.751G>A		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000505973.1	A0A7P0TAF9
CUL4B	ENST00000681333.1 link	n.*258G>A		non_coding_transcript_exon_variant	Exon 9 of 17			ENSP00000505739.1	A0A7P0T9R8
CUL4B	ENST00000681869.1 link	n.751G>A		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000505597.1	A0A7P0T9D0
CUL4B	ENST00000681908.1 link	n.751G>A		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000505777.1	A0A7P0T9P5
CUL4B	ENST00000673919.1 link	n.*756G>A		3_prime_UTR_variant	Exon 10 of 21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679405.1 link	n.*518G>A		3_prime_UTR_variant	Exon 11 of 22			ENSP00000504985.1	A0A7P0Z439
CUL4B	ENST00000679432.1 link	n.*518G>A		3_prime_UTR_variant	Exon 11 of 22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000680918.1 link	n.*225G>A		3_prime_UTR_variant	Exon 7 of 18			ENSP00000505955.1	A0A7P0Z4G9
CUL4B	ENST00000681080.1 link	n.*518G>A		3_prime_UTR_variant	Exon 9 of 20			ENSP00000505898.1	A0A7P0Z4E4
CUL4B	ENST00000681333.1 link	n.*258G>A		3_prime_UTR_variant	Exon 9 of 17			ENSP00000505739.1	A0A7P0T9R8

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000223

AC:

AN:

179477

AF XY:

0.0000155

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000743

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000250

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000369

AC:

AN:

1084033

Hom.:

Cov.:

AF XY:

0.00000285

AC XY:

AN XY:

350737

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

26114

American (AMR)

AF:

0.0000571

AC:

AN:

35009

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19197

East Asian (EAS)

AF:

0.00

AC:

AN:

30039

South Asian (SAS)

AF:

0.00

AC:

AN:

53226

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40400

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4038

European-Non Finnish (NFE)

AF:

0.00000241

AC:

AN:

830402

Other (OTH)

AF:

0.00

AC:

AN:

45608

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.342

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

X-linked intellectual disability Cabezas type

Uncertain:2

Oct 07, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 18, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 455 of the CUL4B protein (p.Ala455Thr). This variant is present in population databases (rs757649304, gnomAD 0.008%), including at least one homozygous and/or hemizygous individual. This variant has not been reported in the literature in individuals affected with CUL4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 434874). 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. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Jan 15, 2016

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Uncertain:1

Dec 28, 2017

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.A455T variant (also known as c.1363G>A), located in coding exon 10 of the CUL4B gene, results from a G to A substitution at nucleotide position 1363. The alanine at codon 455 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.053

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.20

.;.;T

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.86

D;D;D

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.28

T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Benign

0.26

.;.;N

PhyloP100

6.1

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-1.1

N;N;N

REVEL

Benign

0.21

Sift

Benign

0.50

T;T;T

Sift4G

Benign

0.52

T;T;T

Polyphen

0.090

B;.;B

Vest4

0.50

MutPred

0.45

.;.;Gain of ubiquitination at K459 (P = 0.0882);

MVP

0.93

MPC

0.62

ClinPred

0.16

GERP RS

5.6

Varity_R

0.63

gMVP

0.58

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs757649304

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over