rs148700620

Positions:

• chrX-120538205-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001079872.2(CUL4B):​c.1857C>T​(p.Cys619=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00137 in 1,156,497 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 558 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., 36 hem., cov: 23)
  • Exomes 𝑓: 0.0014 (0 hom. 522 hem.)
• Consequence: CUL4B NM_001079872.2 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 1.73

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant X-120538205-G-A is Benign according to our data. Variant chrX-120538205-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 194630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120538205-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.73 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00114 (127/111794) while in subpopulation SAS AF= 0.00476 (13/2730). AF 95% confidence interval is 0.00282. There are 0 homozygotes in gnomad4. There are 36 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Hemizygotes in GnomAd4 at 36 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL4B	NM_001079872.2	c.1857C>T	p.Cys619=	synonymous_variant	14/20	ENST00000371322.11
CUL4B	NM_003588.4	c.1911C>T	p.Cys637=	synonymous_variant	16/22
CUL4B	NM_001330624.2	c.1872C>T	p.Cys624=	synonymous_variant	15/21
CUL4B	NM_001369145.1	c.1323C>T	p.Cys441=	synonymous_variant	14/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL4B	ENST00000371322.11	c.1857C>T	p.Cys619=	synonymous_variant	14/20	1	NM_001079872.2

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 126 AN: 111742 Hom.: 0 Cov.: 23 AF XY: 0.00103 AC XY: 35 AN XY: 33942

Gnomad AFR AF: 0.000227

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000671

Gnomad ASJ AF: 0.00339

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00438

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00847

Gnomad NFE AF: 0.00162

Gnomad OTH AF: 0.00201

GnomAD3 exomes AF: 0.00173 AC: 307 AN: 177961 Hom.: 0 AF XY: 0.00208 AC XY: 131 AN XY: 62851

Gnomad AFR exome AF: 0.000232

Gnomad AMR exome AF: 0.000456

Gnomad ASJ exome AF: 0.00343

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00489

Gnomad FIN exome AF: 0.000192

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.00139 AC: 1453 AN: 1044703 Hom.: 0 Cov.: 23 AF XY: 0.00164 AC XY: 522 AN XY: 318991

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.000462

Gnomad4 ASJ exome AF: 0.00317

Gnomad4 EAS exome AF: 0.0000336

Gnomad4 SAS exome AF: 0.00476

Gnomad4 FIN exome AF: 0.000224

Gnomad4 NFE exome AF: 0.00122

Gnomad4 OTH exome AF: 0.00269

GnomAD4 genome AF: 0.00114 AC: 127 AN: 111794 Hom.: 0 Cov.: 23 AF XY: 0.00106 AC XY: 36 AN XY: 34004

Gnomad4 AFR AF: 0.000227

Gnomad4 AMR AF: 0.000670

Gnomad4 ASJ AF: 0.00339

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00476

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00162

Gnomad4 OTH AF: 0.00198

Alfa AF: 0.00153 Hom.: 10

Bravo AF: 0.00110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Mar 13, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 08, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 06, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 15, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 06, 2017	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 27, 2016

This alteration is classified as 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. -

CUL4B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 05, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.7
DANN	Benign	0.49
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148700620; hg19: chrX-119672060; COSMIC: COSV100340271;