X-120526837-C-T

Position:

• chrX-120526837-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001079872.2(CUL4B):​c.2612G>A​(p.Arg871Lys) 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 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: 7.52

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 Uncertain_significance. Variant got 5 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, 0.92

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2612G>A	p.Arg871Lys	missense_variant	20/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2666G>A	p.Arg889Lys	missense_variant	22/22		NP_003579.3
CUL4B	NM_001330624.2	c.2627G>A	p.Arg876Lys	missense_variant	21/21		NP_001317553.1
CUL4B	NM_001369145.1	c.2078G>A	p.Arg693Lys	missense_variant	20/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2612G>A	p.Arg871Lys	missense_variant	20/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2726G>A	p.Arg909Lys	missense_variant	23/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2666G>A	p.Arg889Lys	missense_variant	22/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2666G>A	p.Arg889Lys	missense_variant	23/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2666G>A	p.Arg889Lys	missense_variant	25/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2627G>A	p.Arg876Lys	missense_variant	21/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2618G>A	p.Arg873Lys	missense_variant	20/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2519G>A	p.Arg840Lys	missense_variant	20/20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2459G>A	p.Arg820Lys	missense_variant	19/19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2267G>A	p.Arg756Lys	missense_variant	21/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2078G>A	p.Arg693Lys	missense_variant	20/20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.1949G>A	p.Arg650Lys	missense_variant	18/18			ENSP00000505239.1
CUL4B	ENST00000680474	c.*58G>A		3_prime_UTR_variant	20/20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2059G>A		non_coding_transcript_exon_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*168G>A		non_coding_transcript_exon_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1821G>A		non_coding_transcript_exon_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1821G>A		non_coding_transcript_exon_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1528G>A		non_coding_transcript_exon_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1821G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*778G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3505G>A		non_coding_transcript_exon_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*784G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2059G>A		3_prime_UTR_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*168G>A		3_prime_UTR_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1821G>A		3_prime_UTR_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1821G>A		3_prime_UTR_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1528G>A		3_prime_UTR_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1821G>A		3_prime_UTR_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*778G>A		3_prime_UTR_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3505G>A		3_prime_UTR_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*784G>A		3_prime_UTR_variant	20/20			ENSP00000505777.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 13, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	.;.;D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.52	D
MutationAssessor	Pathogenic	3.2	.;.;M
PrimateAI	Pathogenic	0.93	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.69
MutPred		0.79		.;.;Gain of relative solvent accessibility (P = 0.0522);
MVP		0.96
MPC		2.8
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.96
gMVP		0.92

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-119660692; COSMIC: COSV104414109;