rs764061992

Variant names:

• chrX-120574605-A-C
• rs764061992
• ENST00000680673.1:c.13T>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003588.4(CUL4B):​c.13T>G​(p.Ser5Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000015 in 1,203,706 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 6 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S5S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000089 (0 hom., 0 hem., cov: 24)
  • Exomes 𝑓: 0.000016 (0 hom. 6 hem.)
• Consequence: CUL4B NM_003588.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.871
• Publications: 1 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ENSG00000302007 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03133288).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.0000156 (17/1091398) while in subpopulation SAS AF = 0.000259 (14/53987). AF 95% confidence interval is 0.000156. There are 0 homozygotes in GnomAdExome4. There are 6 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position passed quality control check.
• BS2: High Hemizygotes in GnomAdExome4 at 6 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003588.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_003588.4		c.13T>G	p.Ser5Ala	missense	Exon 2 of 22	NP_003579.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000680673.1		c.13T>G	p.Ser5Ala	missense	Exon 2 of 22	ENSP00000505084.1	Q13620-2
	CUL4B	ENST00000681253.1		c.13T>G	p.Ser5Ala	missense	Exon 3 of 23	ENSP00000506259.1	Q13620-2
	CUL4B	ENST00000681652.1		c.13T>G	p.Ser5Ala	missense	Exon 5 of 25	ENSP00000505176.1	Q13620-2

Frequencies

GnomAD3 genomes AF: 0.00000890 AC: 1 AN: 112308 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000366

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000490 AC: 9 AN: 183516 AF XY: 0.0000442

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000156 AC: 17 AN: 1091398 Hom.: 0 Cov.: 27 AF XY: 0.0000168 AC XY: 6 AN XY: 356968

African (AFR) AF: 0.00 AC: 0 AN: 26272

American (AMR) AF: 0.00 AC: 0 AN: 35196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19335

East Asian (EAS) AF: 0.00 AC: 0 AN: 30167

South Asian (SAS) AF: 0.000259 AC: 14 AN: 53987

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40517

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4123

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 835932

Other (OTH) AF: 0.0000654 AC: 3 AN: 45869

GnomAD4 genome AF: 0.00000890 AC: 1 AN: 112308 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 34462

African (AFR) AF: 0.00 AC: 0 AN: 30934

American (AMR) AF: 0.00 AC: 0 AN: 10585

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2656

East Asian (EAS) AF: 0.00 AC: 0 AN: 3593

South Asian (SAS) AF: 0.000366 AC: 1 AN: 2731

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6085

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53286

Other (OTH) AF: 0.00 AC: 0 AN: 1513

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.067
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	6.8
DANN	Benign	0.63
DEOGEN2	Benign	0.072	T
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.24	T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.031	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.87
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.030	N
REVEL	Benign	0.12
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.043	D
Polyphen		0.14	B
Vest4		0.092
MutPred		0.090		Loss of phosphorylation at S5 (P = 0.004)
MVP		0.60
MPC		0.61
ClinPred		0.093	T
GERP RS		2.0
Varity_R		0.36
gMVP		0.059
Mutation Taster		=99/1	polymorphism

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

Other links and lift over

dbSNP: rs764061992; hg19: chrX-119708460;