dbSNP rs121434615: CUL4B:p.Arg554Cys (chrX-120539349-G-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2PP3_StrongPP5_Moderate

The NM_001079872.2(CUL4B):c.1660C>T(p.Arg554Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

Frequency

Genomes: not found (cov: 23)

Exomes 𝑓: 0.0 ( 0 hom. 0 hem. )

Failed GnomAD Quality Control

Consequence

CUL4B
NM_001079872.2 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:2

Conservation

PhyloP100: 6.29

Publications

7 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: Likely_pathogenic. The variant received 8 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.988

PP5

Variant X-120539349-G-A is Pathogenic according to our data. Variant chrX-120539349-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11338.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1660C>T	p.Arg554Cys	missense	Exon 12 of 20	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4		c.1714C>T	p.Arg572Cys	missense	Exon 14 of 22	NP_003579.3
CUL4B	NM_001330624.2		c.1675C>T	p.Arg559Cys	missense	Exon 13 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.1660C>T	p.Arg554Cys	missense	Exon 12 of 20	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1		c.1774C>T	p.Arg592Cys	missense	Exon 15 of 23	ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1		c.1714C>T	p.Arg572Cys	missense	Exon 14 of 22	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0;AS_VQSR

AF:

0.00

AC:

AN:

1078117

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

345055

African (AFR)

AF:

0.00

AC:

AN:

26008

American (AMR)

AF:

0.00

AC:

AN:

34583

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19135

East Asian (EAS)

AF:

0.00

AC:

AN:

30029

South Asian (SAS)

AF:

0.00

AC:

AN:

52454

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40173

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4084

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

826314

Other (OTH)

AF:

0.00

AC:

AN:

45337

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.52

BayesDel_noAF

Pathogenic

0.50

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.97

MetaRNN

Pathogenic

0.99

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.7

PhyloP100

6.3

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-7.7

REVEL

Pathogenic

0.91

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.80

MutPred

0.91

Loss of MoRF binding (P = 0.0249)

MVP

0.99

MPC

3.5

ClinPred

1.0

GERP RS

5.7

Varity_R

0.97

gMVP

0.88

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over