rs1556199349

Variant names:

• chrX-120538203-C-A
• rs1556199349
• NM_001079872.2:c.1859G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001079872.2(CUL4B):​c.1859G>T​(p.Gly620Val) 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. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.88
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1859G>T	p.Gly620Val	missense_variant	Exon 14 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1913G>T	p.Gly638Val	missense_variant	Exon 16 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.1874G>T	p.Gly625Val	missense_variant	Exon 15 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.1325G>T	p.Gly442Val	missense_variant	Exon 14 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1859G>T	p.Gly620Val	missense_variant	Exon 14 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1973G>T	p.Gly658Val	missense_variant	Exon 17 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1913G>T	p.Gly638Val	missense_variant	Exon 16 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1913G>T	p.Gly638Val	missense_variant	Exon 17 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1913G>T	p.Gly638Val	missense_variant	Exon 19 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1874G>T	p.Gly625Val	missense_variant	Exon 15 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1859G>T	p.Gly620Val	missense_variant	Exon 14 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1766G>T	p.Gly589Val	missense_variant	Exon 14 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1859G>T	p.Gly620Val	missense_variant	Exon 14 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1514G>T	p.Gly505Val	missense_variant	Exon 15 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1325G>T	p.Gly442Val	missense_variant	Exon 14 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1301G>T	p.Gly434Val	missense_variant	Exon 13 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.1196G>T	p.Gly399Val	missense_variant	Exon 12 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*1306G>T		non_coding_transcript_exon_variant	Exon 15 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1301G>T		non_coding_transcript_exon_variant	Exon 13 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1068G>T		non_coding_transcript_exon_variant	Exon 16 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1068G>T		non_coding_transcript_exon_variant	Exon 16 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*775G>T		non_coding_transcript_exon_variant	Exon 12 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1068G>T		non_coding_transcript_exon_variant	Exon 14 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*25G>T		non_coding_transcript_exon_variant	Exon 14 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2752G>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.1301G>T		non_coding_transcript_exon_variant	Exon 13 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.1301G>T		non_coding_transcript_exon_variant	Exon 13 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1306G>T		3_prime_UTR_variant	Exon 15 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*1068G>T		3_prime_UTR_variant	Exon 16 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1068G>T		3_prime_UTR_variant	Exon 16 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*775G>T		3_prime_UTR_variant	Exon 12 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1068G>T		3_prime_UTR_variant	Exon 14 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*25G>T		3_prime_UTR_variant	Exon 14 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*2752G>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000505739.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 23

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 01, 2017

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.59	D
BayesDel_noAF	Pathogenic	0.61
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;.;D
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.1	.;.;H
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-8.3	D;D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.88
MutPred		0.96		.;.;Loss of disorder (P = 0.0402);
MVP		0.98
MPC		3.3
ClinPred		1.0	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		1.0
gMVP		0.98
Mutation Taster		=33/67	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1556199349; hg19: chrX-119672058;