X-120560576-T-A

Variant names:

• chrX-120560576-T-A
• rs757541076
• NM_001079872.2:c.63A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079872.2(CUL4B):​c.63A>T​(p.Arg21Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000365 in 1,095,284 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R21T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 0 hem.)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.22
• 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

ENSG00000302007 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34952393).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.63A>T	p.Arg21Ser	missense_variant	Exon 1 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.117A>T	p.Arg39Ser	missense_variant	Exon 3 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.78A>T	p.Arg26Ser	missense_variant	Exon 2 of 21		NP_001317553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.63A>T	p.Arg21Ser	missense_variant	Exon 1 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.78A>T	p.Arg26Ser	missense_variant	Exon 2 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.117A>T	p.Arg39Ser	missense_variant	Exon 3 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.117A>T	p.Arg39Ser	missense_variant	Exon 4 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.117A>T	p.Arg39Ser	missense_variant	Exon 6 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.78A>T	p.Arg26Ser	missense_variant	Exon 2 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.63A>T	p.Arg21Ser	missense_variant	Exon 1 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.63A>T	p.Arg21Ser	missense_variant	Exon 1 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.63A>T	p.Arg21Ser	missense_variant	Exon 1 of 19	1		ENSP00000384109.4
CUL4B	ENST00000673919.1	n.63A>T		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000500994.1
CUL4B	ENST00000679432.1	n.48A>T		non_coding_transcript_exon_variant	Exon 1 of 22			ENSP00000505343.1
CUL4B	ENST00000681333.1	n.63A>T		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000505739.1
CUL4B	ENST00000679927.1	c.-283A>T		5_prime_UTR_variant	Exon 2 of 21			ENSP00000505603.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000170 AC: 3 AN: 176094 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000112

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000365 AC: 4 AN: 1095284 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 361082

African (AFR) AF: 0.00 AC: 0 AN: 26378

American (AMR) AF: 0.000114 AC: 4 AN: 34968

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19355

East Asian (EAS) AF: 0.00 AC: 0 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 53780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39729

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3756

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841179

Other (OTH) AF: 0.00 AC: 0 AN: 45961

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked intellectual disability Cabezas type Uncertain:1

Apr 10, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a rare missense change with uncertain impact on 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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant is present in population databases (rs757541076, ExAC 0.01%) but has not been reported in the literature in individuals with a CUL4B-related disease. This sequence change replaces arginine with serine at codon 39 of the CUL4B protein (p.Arg39Ser). The arginine residue is moderately conserved and there is a moderate physicochemical difference between arginine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.0029	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.086	.;.;T
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Uncertain	0.93	D;D;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.81	.;.;L
PhyloP100		3.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.22	N;N;N
REVEL	Uncertain	0.32
Sift	Benign	0.044	D;D;D
Sift4G	Benign	1.0	T;T;T
Polyphen		0.98	D;.;D
Vest4		0.43
MutPred		0.25		.;.;Gain of glycosylation at R39 (P = 0.0058);
MVP		0.95
MPC		0.77
ClinPred		0.36	T
GERP RS		5.6
PromoterAI		-0.0081	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.34
Mutation Taster		=82/18	polymorphism

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: rs757541076; hg19: chrX-119694431;