rs1556213268

Positions:

• chrX-120544181-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001079872.2(CUL4B):​c.1106A>G​(p.Gln369Arg) 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 benign outcome for this variant. 12/20 in silico tools predict a benign 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: 7.95

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 2 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.32139373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1106A>G	p.Gln369Arg	missense_variant	7/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1160A>G	p.Gln387Arg	missense_variant	9/22		NP_003579.3
CUL4B	NM_001330624.2	c.1121A>G	p.Gln374Arg	missense_variant	8/21		NP_001317553.1
CUL4B	NM_001369145.1	c.572A>G	p.Gln191Arg	missense_variant	7/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1106A>G	p.Gln369Arg	missense_variant	7/20	1	NM_001079872.2	ENSP00000360373

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 23

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2017

This sequence change replaces glutamine with arginine at codon 387 of the CUL4B protein (p.Gln387Arg). The glutamine residue is moderately conserved and there is a small physicochemical difference between glutamine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CUL4B-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.029	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.16	.;.;T;T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.32	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.080	.;.;N;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.63	N;N;N;N
REVEL	Benign	0.21
Sift	Benign	0.50	T;T;T;T
Sift4G	Benign	0.58	T;T;T;.
Polyphen		0.0	B;.;B;.
Vest4		0.31
MutPred		0.30		.;.;Gain of phosphorylation at S384 (P = 0.1172);.;
MVP		0.88
MPC		0.68
ClinPred		0.65	D
GERP RS		5.7
Varity_R		0.64
gMVP		0.74

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: rs1556213268; hg19: chrX-119678036;