chrX-120560261-T-TGAG

Variant names:

• chrX-120560261-T-TGAG
• rs754330779
• NM_001079872.2:c.375_377dupCTC

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3 BP6_Very_Strong BS2

The NM_001079872.2(CUL4B):​c.375_377dupCTC​(p.Ser126dup) variant causes a disruptive inframe insertion change. The variant allele was found at a frequency of 0.0000306 in 1,208,157 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000054 (0 hom., 2 hem., cov: 22)
  • Exomes 𝑓: 0.000028 (0 hom. 8 hem.)
• Consequence: CUL4B NM_001079872.2 disruptive_inframe_insertion
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts U:1 B:3
• Conservation: PhyloP100: 4.84

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001079872.2
• BP6: Variant X-120560261-T-TGAG is Benign according to our data. Variant chrX-120560261-T-TGAG is described in ClinVar as [Likely_benign]. Clinvar id is 420582.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 3 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	Exon 2 of 21		NP_001317553.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	Exon 2 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 3 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 4 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	Exon 6 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	Exon 2 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	Exon 1 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.30_32dupCTC	p.Ser11dup	disruptive_inframe_insertion	Exon 2 of 21			ENSP00000505603.1
CUL4B	ENST00000673919.1	n.375_377dupCTC		non_coding_transcript_exon_variant	Exon 1 of 21			ENSP00000500994.1
CUL4B	ENST00000679432.1	n.360_362dupCTC		non_coding_transcript_exon_variant	Exon 1 of 22			ENSP00000505343.1
CUL4B	ENST00000681333.1	n.375_377dupCTC		non_coding_transcript_exon_variant	Exon 1 of 17			ENSP00000505739.1

Frequencies

GnomAD3 genomes AF: 0.0000540 AC: 6 AN: 111014 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33340

Gnomad AFR AF: 0.0000982

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: 0.0000378

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000404 AC: 7 AN: 173145 Hom.: 0 AF XY: 0.0000325 AC XY: 2 AN XY: 61627

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.000139

Gnomad EAS exome AF: 0.000154

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000128

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000283 AC: 31 AN: 1097143 Hom.: 0 Cov.: 33 AF XY: 0.0000220 AC XY: 8 AN XY: 362877

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000852

Gnomad4 ASJ exome AF: 0.0000516

Gnomad4 EAS exome AF: 0.000132

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000262

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000540 AC: 6 AN: 111014 Hom.: 0 Cov.: 22 AF XY: 0.0000600 AC XY: 2 AN XY: 33340

Gnomad4 AFR AF: 0.0000982

Gnomad4 AMR AF: 0.0000958

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000378

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

CUL4B-related disorder Uncertain:1

May 02, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The CUL4B c.429_431dupCTC variant is predicted to result in an in-frame duplication (p.Ser146dup). This variant was reported in an individual with intellectual disability and additional features consistent with CUL4B-related disease (Tzschach et al 2015. PubMed ID: 25649377). This variant is reported in 0.014% of alleles in individuals of East Asian descent in gnomAD, including three hemizygotes. The gnomAD data suggest it is less likely that this is a pathogenic variant. However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Sep 01, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

X-linked intellectual disability Cabezas type Benign:1

May 16, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Benign:1

Sep 06, 2017

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs754330779; hg19: chrX-119694116;