rs754330779

Variant names:

• chrX-120560261-TGAGGAGGAG-T
• rs754330779
• NM_001079872.2:c.369_377delCTCCTCCTC

Your query was ambiguous. Multiple possible variants found:

• chrX-120560261-TGAGGAGGAG-T
• chrX-120560261-TGAGGAGGAG-TGAG
• chrX-120560261-TGAGGAGGAG-TGAGGAG
• chrX-120560261-TGAGGAGGAG-TGAGGAGGAGGAG
• chrX-120560261-TGAGGAGGAG-TGAGGAGGAGGAGGAG

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PP3 PP5 BP3 BS2

The NM_001079872.2(CUL4B):​c.369_377delCTCCTCCTC​(p.Ser124_Ser126del) variant causes a disruptive inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000447 in 1,208,215 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 16 hemizygotes in GnomAD. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000063 (0 hom., 1 hem., cov: 22)
  • Exomes 𝑓: 0.000043 (0 hom. 15 hem.)
• Consequence: CUL4B NM_001079872.2 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.26
• 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: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PP3: No computational evidence supports a deleterious effect, but strongly conserved according to phyloP
• PP5: Variant X-120560261-TGAGGAGGAG-T is Pathogenic according to our data. Variant chrX-120560261-TGAGGAGGAG-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 504176.
• BP3: Nonframeshift variant in repetitive region in NM_001079872.2
• BS2: High Hemizygotes in GnomAdExome4 at 15 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20	NP_001073341.1
	CUL4B	NM_003588.4		c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 3 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.384_392delCTCCTCCTC	p.Ser129_Ser131del	disruptive_inframe_deletion	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.369_377delCTCCTCCTC	p.Ser124_Ser126del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.384_392delCTCCTCCTC	p.Ser129_Ser131del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.423_431delCTCCTCCTC	p.Ser142_Ser144del	disruptive_inframe_deletion	Exon 3 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes AF: 0.0000631 AC: 7 AN: 111015 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000958

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: 0.000113

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000231 AC: 4 AN: 173145 AF XY: 0.00

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: 0.0000514

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000428 AC: 47 AN: 1097200 Hom.: 0 AF XY: 0.0000413 AC XY: 15 AN XY: 362924

African (AFR) AF: 0.00 AC: 0 AN: 26382

American (AMR) AF: 0.00 AC: 0 AN: 35197

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19372

East Asian (EAS) AF: 0.00 AC: 0 AN: 30195

South Asian (SAS) AF: 0.00 AC: 0 AN: 54099

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40449

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4133

European-Non Finnish (NFE) AF: 0.0000559 AC: 47 AN: 841308

Other (OTH) AF: 0.00 AC: 0 AN: 46065

GnomAD4 genome AF: 0.0000631 AC: 7 AN: 111015 Hom.: 0 Cov.: 22 AF XY: 0.0000300 AC XY: 1 AN XY: 33341

African (AFR) AF: 0.00 AC: 0 AN: 30539

American (AMR) AF: 0.0000958 AC: 1 AN: 10437

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2637

East Asian (EAS) AF: 0.00 AC: 0 AN: 3537

South Asian (SAS) AF: 0.00 AC: 0 AN: 2654

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 237

European-Non Finnish (NFE) AF: 0.000113 AC: 6 AN: 52899

Other (OTH) AF: 0.00 AC: 0 AN: 1493

Alfa AF: 0.0000434 Hom.: 0

Bravo AF: 0.0000302

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	CUL4B-related disorder (1)
1	-	-	not provided (1)
-	1	-	X-linked intellectual disability Cabezas type (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs754330779; hg19: chrX-119694116;