rs757541076

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).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079872.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

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

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.63A>T	p.Arg21Ser	missense	Exon 1 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.78A>T	p.Arg26Ser	missense	Exon 2 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.117A>T	p.Arg39Ser	missense	Exon 3 of 22	ENSP00000505084.1

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

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	0.81	L
PhyloP100		3.2
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.22	N
REVEL	Uncertain	0.32
Sift	Benign	0.044	D
Sift4G	Benign	1.0	T
Polyphen		0.98	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;