X-120560261-T-TGAG

Position:

chrX-120560261-T-TGAG

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP3BP6_Very_StrongBS2

The ENST00000371322.11(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 (★★). Synonymous variant affecting the same amino acid position (i.e. S126S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 2 hem., cov: 22)

Exomes 𝑓: 0.000028 ( 0 hom. 8 hem. )

Consequence

CUL4B
ENST00000371322.11 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts U:1B:3

Conservation

PhyloP100: 4.84

Variant links:

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 links:

CUL4B (HGNC:):

CUL4B links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP3

Nonframeshift variant in repetitive region in ENST00000371322.11

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/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2 linkuse as main transcript	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	1/20	ENST00000371322.11	NP_001073341.1	Q13620-1
CUL4B	NM_003588.4 linkuse as main transcript	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	3/22		NP_003579.3	Q13620-2
CUL4B	NM_001330624.2 linkuse as main transcript	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	2/21		NP_001317553.1	K4DI93

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CUL4B	ENST00000371322.11 linkuse as main transcript	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	1/20	1	NM_001079872.2	ENSP00000360373.5	Q13620-1
CUL4B	ENST00000681206.1 linkuse as main transcript	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	2/23			ENSP00000505480.1	A0A7P0T954
CUL4B	ENST00000680673.1 linkuse as main transcript	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	3/22			ENSP00000505084.1	Q13620-2
CUL4B	ENST00000681253.1 linkuse as main transcript	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	4/23			ENSP00000506259.1	Q13620-2
CUL4B	ENST00000681652.1 linkuse as main transcript	c.429_431dupCTC	p.Ser144dup	disruptive_inframe_insertion	6/25			ENSP00000505176.1	Q13620-2
CUL4B	ENST00000336592.11 linkuse as main transcript	c.390_392dupCTC	p.Ser131dup	disruptive_inframe_insertion	2/21	5		ENSP00000338919.6	K4DI93
CUL4B	ENST00000674137.11 linkuse as main transcript	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	1/20			ENSP00000501019.6	A0A669KAX4
CUL4B	ENST00000681090.1 linkuse as main transcript	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	1/20			ENSP00000506288.1	A0A7P0TAQ3
CUL4B	ENST00000404115.8 linkuse as main transcript	c.375_377dupCTC	p.Ser126dup	disruptive_inframe_insertion	1/19	1		ENSP00000384109.4	A0A804CL36
CUL4B	ENST00000679927.1 linkuse as main transcript	c.30_32dupCTC	p.Ser11dup	disruptive_inframe_insertion	2/21			ENSP00000505603.1	A0A7P0T9L3
CUL4B	ENST00000673919.1 linkuse as main transcript	n.375_377dupCTC		non_coding_transcript_exon_variant	1/21			ENSP00000500994.1	A0A669KAU9
CUL4B	ENST00000679432.1 linkuse as main transcript	n.360_362dupCTC		non_coding_transcript_exon_variant	1/22			ENSP00000505343.1	A0A7P0T8W4
CUL4B	ENST00000681333.1 linkuse as main transcript	n.375_377dupCTC		non_coding_transcript_exon_variant	1/17			ENSP00000505739.1	A0A7P0T9R8

Frequencies

GnomAD3 genomes

AF:

0.0000540

AC:

AN:

111014

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33340

show subpopulations

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:

AN:

173145

Hom.:

AF XY:

0.0000325

AC XY:

AN XY:

61627

show subpopulations

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:

AN:

1097143

Hom.:

Cov.:

AF XY:

0.0000220

AC XY:

AN XY:

362877

show subpopulations

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:

AN:

111014

Hom.:

Cov.:

AF XY:

0.0000600

AC XY:

AN XY:

33340

show subpopulations

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:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

CUL4B-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 02, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 01, 2016

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 16, 2023

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 06, 2017

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

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over