chrX-120526815-C-T

Variant names:

• chrX-120526815-C-T
• rs143580749
• NM_001079872.2:c.2634G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001079872.2(CUL4B):​c.2634G>A​(p.Arg878Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,195,173 control chromosomes in the GnomAD database, including 4 homozygotes. There are 181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., 87 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (2 hom. 94 hem.)
• Consequence: CUL4B NM_001079872.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.118
• 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-120526815-C-T is Benign according to our data. Variant chrX-120526815-C-T is described in ClinVar as Benign. ClinVar VariationId is 506496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.118 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00359 (401/111776) while in subpopulation AFR AF = 0.0127 (390/30807). AF 95% confidence interval is 0.0116. There are 2 homozygotes in GnomAd4. There are 87 alleles in the male GnomAd4 subpopulation. Median coverage is 23. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.2634G>A	p.Arg878Arg	synonymous	Exon 20 of 20	NP_001073341.1	Q13620-1
	CUL4B	NM_003588.4		c.2688G>A	p.Arg896Arg	synonymous	Exon 22 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.2649G>A	p.Arg883Arg	synonymous	Exon 21 of 21	NP_001317553.1	K4DI93

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.2634G>A	p.Arg878Arg	synonymous	Exon 20 of 20	ENSP00000360373.5	Q13620-1
	CUL4B	ENST00000681206.1		c.2748G>A	p.Arg916Arg	synonymous	Exon 23 of 23	ENSP00000505480.1	A0A7P0T954
	CUL4B	ENST00000680673.1		c.2688G>A	p.Arg896Arg	synonymous	Exon 22 of 22	ENSP00000505084.1	Q13620-2

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 399 AN: 111724 Hom.: 2 Cov.: 23

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00268

GnomAD2 exomes AF: 0.000908 AC: 166 AN: 182828 AF XY: 0.000445

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000365

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: 0.000443

GnomAD4 exome AF: 0.000382 AC: 414 AN: 1083397 Hom.: 2 Cov.: 26 AF XY: 0.000268 AC XY: 94 AN XY: 350503

African (AFR) AF: 0.0137 AC: 356 AN: 26048

American (AMR) AF: 0.000487 AC: 17 AN: 34914

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19025

East Asian (EAS) AF: 0.00 AC: 0 AN: 29621

South Asian (SAS) AF: 0.0000372 AC: 2 AN: 53746

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4072

European-Non Finnish (NFE) AF: 0.00000361 AC: 3 AN: 831265

Other (OTH) AF: 0.000794 AC: 36 AN: 45342

GnomAD4 genome AF: 0.00359 AC: 401 AN: 111776 Hom.: 2 Cov.: 23 AF XY: 0.00256 AC XY: 87 AN XY: 33982

African (AFR) AF: 0.0127 AC: 390 AN: 30807

American (AMR) AF: 0.000665 AC: 7 AN: 10520

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2641

East Asian (EAS) AF: 0.00 AC: 0 AN: 3560

South Asian (SAS) AF: 0.00 AC: 0 AN: 2745

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5970

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 218

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53118

Other (OTH) AF: 0.00264 AC: 4 AN: 1513

Alfa AF: 0.00204 Hom.: 6

Bravo AF: 0.00399

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)
-	-	1	X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.0
DANN	Benign	0.55
PhyloP100		0.12
Mutation Taster		=97/3	polymorphism (auto)

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: rs143580749; hg19: chrX-119660670;