X-120560261-TGAG-T

Variant names:

• chrX-120560261-TGAG-T
• rs754330779
• NM_001079872.2:c.375_377delCTC

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_003588.4(CUL4B):​c.429_431delCTC​(p.Ser144del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000816 in 1,176,913 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 14 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000045 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000085 (0 hom. 12 hem.)
• Consequence: CUL4B NM_003588.4 disruptive_inframe_deletion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.25
• 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: Benign. The variant received -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_003588.4
• BP6: Variant X-120560261-TGAG-T is Benign according to our data. Variant chrX-120560261-TGAG-T is described in ClinVar as Likely_benign. ClinVar VariationId is 418570.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.375_377delCTC	p.Ser126del	disruptive_inframe_deletion	Exon 1 of 20	NP_001073341.1
	CUL4B	NM_003588.4		c.429_431delCTC	p.Ser144del	disruptive_inframe_deletion	Exon 3 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.390_392delCTC	p.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.375_377delCTC	p.Ser126del	disruptive_inframe_deletion	Exon 1 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.390_392delCTC	p.Ser131del	disruptive_inframe_deletion	Exon 2 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.429_431delCTC	p.Ser144del	disruptive_inframe_deletion	Exon 3 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes AF: 0.0000451 AC: 5 AN: 110981 Hom.: 0 Cov.: 22

Gnomad AFR AF: 0.0000655

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000959

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000520 AC: 9 AN: 173145 AF XY: 0.0000162

Gnomad AFR exome AF: 0.0000795

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000340

Gnomad NFE exome AF: 0.0000385

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000854 AC: 91 AN: 1065932 Hom.: 0 AF XY: 0.0000345 AC XY: 12 AN XY: 347582

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000777 AC: 2 AN: 25754

American (AMR) AF: 0.00 AC: 0 AN: 34439

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18878

East Asian (EAS) AF: 0.0000340 AC: 1 AN: 29416

South Asian (SAS) AF: 0.0000769 AC: 4 AN: 52025

European-Finnish (FIN) AF: 0.0000761 AC: 3 AN: 39421

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4041

European-Non Finnish (NFE) AF: 0.0000930 AC: 76 AN: 817132

Other (OTH) AF: 0.000112 AC: 5 AN: 44826

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000451 AC: 5 AN: 110981 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33321

African (AFR) AF: 0.0000655 AC: 2 AN: 30535

American (AMR) AF: 0.0000959 AC: 1 AN: 10432

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: 5886

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

European-Non Finnish (NFE) AF: 0.0000378 AC: 2 AN: 52886

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

Alfa AF: 0.00816 Hom.: 0

Asia WGS AF: 0.00438 AC: 11 AN: 2522

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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		5.2
Mutation Taster		=79/21	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: rs754330779; hg19: chrX-119694116; COSMIC: COSV60686673; COSMIC: COSV60686673;