rs750866615

Variant names:

• chrX-120543782-T-G
• rs750866615
• NM_001079872.2:c.1201A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001079872.2(CUL4B):​c.1201A>C​(p.Lys401Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.12

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1201A>C	p.Lys401Gln	missense_variant	Exon 8 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1255A>C	p.Lys419Gln	missense_variant	Exon 10 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.1216A>C	p.Lys406Gln	missense_variant	Exon 9 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.667A>C	p.Lys223Gln	missense_variant	Exon 8 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1201A>C	p.Lys401Gln	missense_variant	Exon 8 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1315A>C	p.Lys439Gln	missense_variant	Exon 11 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1255A>C	p.Lys419Gln	missense_variant	Exon 10 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1255A>C	p.Lys419Gln	missense_variant	Exon 11 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1255A>C	p.Lys419Gln	missense_variant	Exon 13 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1216A>C	p.Lys406Gln	missense_variant	Exon 9 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1201A>C	p.Lys401Gln	missense_variant	Exon 8 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1108A>C	p.Lys370Gln	missense_variant	Exon 8 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1201A>C	p.Lys401Gln	missense_variant	Exon 8 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.856A>C	p.Lys286Gln	missense_variant	Exon 9 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.667A>C	p.Lys223Gln	missense_variant	Exon 8 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.643A>C	p.Lys215Gln	missense_variant	Exon 7 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.643A>C	p.Lys215Gln	missense_variant	Exon 7 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*648A>C		non_coding_transcript_exon_variant	Exon 9 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.643A>C		non_coding_transcript_exon_variant	Exon 7 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*410A>C		non_coding_transcript_exon_variant	Exon 10 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*410A>C		non_coding_transcript_exon_variant	Exon 10 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*117A>C		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*410A>C		non_coding_transcript_exon_variant	Exon 8 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.643A>C		non_coding_transcript_exon_variant	Exon 7 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*150A>C		non_coding_transcript_exon_variant	Exon 8 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.643A>C		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.643A>C		non_coding_transcript_exon_variant	Exon 7 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*648A>C		3_prime_UTR_variant	Exon 9 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*410A>C		3_prime_UTR_variant	Exon 10 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*410A>C		3_prime_UTR_variant	Exon 10 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*117A>C		3_prime_UTR_variant	Exon 6 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*410A>C		3_prime_UTR_variant	Exon 8 of 20			ENSP00000505898.1
CUL4B	ENST00000681333.1	n.*150A>C		3_prime_UTR_variant	Exon 8 of 17			ENSP00000505739.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD3 exomes AF: 0.00000546 AC: 1 AN: 183074 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 67656

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000122

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Dec 23, 2014

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

X-linked intellectual disability Cabezas type Uncertain:1

Nov 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces lysine, which is basic and polar, with glutamine, which is neutral and polar, at codon 419 of the CUL4B protein (p.Lys419Gln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with CUL4B-related conditions. ClinVar contains an entry for this variant (Variation ID: 210808). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on CUL4B protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	0.0045	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.49	.;.;T;T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.096	D
MetaRNN	Uncertain	0.58	D;D;D;D
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.83	.;.;L;.
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.039	D;T;T;D
Sift4G	Benign	0.12	T;T;T;.
Polyphen		0.86	P;.;P;.
Vest4		0.47
MutPred		0.48		.;.;Loss of ubiquitination at K419 (P = 0.0134);.;
MVP		0.91
MPC		0.70
ClinPred		0.91	D
GERP RS		4.8
Varity_R		0.90
gMVP		0.78

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: rs750866615; hg19: chrX-119677637;