X-120543779-G-C

Position:

• chrX-120543779-G-C

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.1204C>G​(p.Arg402Gly) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.88

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.943
• PP5: Variant X-120543779-G-C is Pathogenic according to our data. Variant chrX-120543779-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 520600.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-120543779-G-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1204C>G	p.Arg402Gly	missense_variant	8/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1258C>G	p.Arg420Gly	missense_variant	10/22		NP_003579.3
CUL4B	NM_001330624.2	c.1219C>G	p.Arg407Gly	missense_variant	9/21		NP_001317553.1
CUL4B	NM_001369145.1	c.670C>G	p.Arg224Gly	missense_variant	8/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1204C>G	p.Arg402Gly	missense_variant	8/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1318C>G	p.Arg440Gly	missense_variant	11/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1258C>G	p.Arg420Gly	missense_variant	10/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1258C>G	p.Arg420Gly	missense_variant	11/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1258C>G	p.Arg420Gly	missense_variant	13/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1219C>G	p.Arg407Gly	missense_variant	9/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1204C>G	p.Arg402Gly	missense_variant	8/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1111C>G	p.Arg371Gly	missense_variant	8/20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1204C>G	p.Arg402Gly	missense_variant	8/19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.859C>G	p.Arg287Gly	missense_variant	9/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.670C>G	p.Arg224Gly	missense_variant	8/20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.646C>G	p.Arg216Gly	missense_variant	7/20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.646C>G	p.Arg216Gly	missense_variant	7/18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*651C>G		non_coding_transcript_exon_variant	9/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.646C>G		non_coding_transcript_exon_variant	7/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*413C>G		non_coding_transcript_exon_variant	10/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*413C>G		non_coding_transcript_exon_variant	10/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*120C>G		non_coding_transcript_exon_variant	6/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*413C>G		non_coding_transcript_exon_variant	8/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.646C>G		non_coding_transcript_exon_variant	7/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*153C>G		non_coding_transcript_exon_variant	8/17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.646C>G		non_coding_transcript_exon_variant	7/17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.646C>G		non_coding_transcript_exon_variant	7/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*651C>G		3_prime_UTR_variant	9/21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*413C>G		3_prime_UTR_variant	10/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*413C>G		3_prime_UTR_variant	10/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*120C>G		3_prime_UTR_variant	6/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*413C>G		3_prime_UTR_variant	8/20			ENSP00000505898.1
CUL4B	ENST00000681333.1	n.*153C>G		3_prime_UTR_variant	8/17			ENSP00000505739.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 13, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	.;.;D;D
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.95	D;D;D;D
M_CAP	Pathogenic	0.92	D
MetaRNN	Pathogenic	0.94	D;D;D;D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.7	.;.;H;.
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-6.6	D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.0080	D;D;D;.
Polyphen		1.0	D;.;D;.
Vest4		0.86
MutPred		0.75		.;.;Gain of glycosylation at K419 (P = 0.0502);.;
MVP		0.99
MPC		1.9
ClinPred		1.0	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.98

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

Other links and lift over

dbSNP: rs1260356990; hg19: chrX-119677634;