X-120526816-C-T

Position:

• chrX-120526816-C-T

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.2633G>A​(p.Arg878Gln) 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: 24)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.57

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 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, 0.965
• PP5: Variant X-120526816-C-T is Pathogenic according to our data. Variant chrX-120526816-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 434871.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2633G>A	p.Arg878Gln	missense_variant	20/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2687G>A	p.Arg896Gln	missense_variant	22/22		NP_003579.3
CUL4B	NM_001330624.2	c.2648G>A	p.Arg883Gln	missense_variant	21/21		NP_001317553.1
CUL4B	NM_001369145.1	c.2099G>A	p.Arg700Gln	missense_variant	20/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2633G>A	p.Arg878Gln	missense_variant	20/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2747G>A	p.Arg916Gln	missense_variant	23/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2687G>A	p.Arg896Gln	missense_variant	22/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2687G>A	p.Arg896Gln	missense_variant	23/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2687G>A	p.Arg896Gln	missense_variant	25/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2648G>A	p.Arg883Gln	missense_variant	21/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2639G>A	p.Arg880Gln	missense_variant	20/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2540G>A	p.Arg847Gln	missense_variant	20/20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2480G>A	p.Arg827Gln	missense_variant	19/19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2288G>A	p.Arg763Gln	missense_variant	21/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2099G>A	p.Arg700Gln	missense_variant	20/20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.1970G>A	p.Arg657Gln	missense_variant	18/18			ENSP00000505239.1
CUL4B	ENST00000680474	c.*79G>A		3_prime_UTR_variant	20/20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2080G>A		non_coding_transcript_exon_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*189G>A		non_coding_transcript_exon_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1842G>A		non_coding_transcript_exon_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1842G>A		non_coding_transcript_exon_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1549G>A		non_coding_transcript_exon_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1842G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*799G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3526G>A		non_coding_transcript_exon_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*805G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2080G>A		3_prime_UTR_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*189G>A		3_prime_UTR_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1842G>A		3_prime_UTR_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1842G>A		3_prime_UTR_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1549G>A		3_prime_UTR_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1842G>A		3_prime_UTR_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*799G>A		3_prime_UTR_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3526G>A		3_prime_UTR_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*805G>A		3_prime_UTR_variant	20/20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Pettigrew syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 16, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.64	.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Pathogenic	2.9	.;.;M
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.70
MutPred		0.84		.;.;Loss of MoRF binding (P = 0.1064);
MVP		0.92
MPC		3.1
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.94
gMVP		0.84

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: rs1556173896; hg19: chrX-119660671;