rs121434615

chrX-120539349-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_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. 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
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.29

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, CUL4B
• 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 id is 11338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL4B	NM_001079872.2	c.1660C>T	p.Arg554Cys	missense_variant	12/20	ENST00000371322.11
CUL4B	NM_003588.4	c.1714C>T	p.Arg572Cys	missense_variant	14/22
CUL4B	NM_001330624.2	c.1675C>T	p.Arg559Cys	missense_variant	13/21
CUL4B	NM_001369145.1	c.1126C>T	p.Arg376Cys	missense_variant	12/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL4B	ENST00000371322.11	c.1660C>T	p.Arg554Cys	missense_variant	12/20	1	NM_001079872.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1078117 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 345055

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: 0.00

GnomAD4 genome Cov.: 23

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2007

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jul 03, 2023

Published functional studies demonstrate a damaging effect to protein function (Nakagawa et al., 2011; Wang et al., 2013); Not observed in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 21816345, 23348097, 20064923, 19377476, 17236139, 28454995) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationTaster	Benign	1.0	A;A;A
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.91		.;.;Loss of MoRF binding (P = 0.0249);
MVP		0.99
MPC		3.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88

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

LitVar

Other links and lift over

dbSNP: rs121434615; hg19: chrX-119673204; COSMIC: COSV105205898; COSMIC: COSV105205898;