rs143580749

Positions:

• chrX-120526815-C-T

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.2634G>A​(p.Arg878Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000682 in 1,195,173 control chromosomes in the GnomAD database, including 4 homozygotes. There are 181 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (2 hom., 87 hem., cov: 23)
  • Exomes 𝑓: 0.00038 (2 hom. 94 hem.)
• Consequence: CUL4B NM_001079872.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.118

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant X-120526815-C-T is Benign according to our data. Variant chrX-120526815-C-T is described in ClinVar as [Benign]. Clinvar id is 506496.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.118 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00359 (401/111776) while in subpopulation AFR AF= 0.0127 (390/30807). AF 95% confidence interval is 0.0116. There are 2 homozygotes in gnomad4. There are 87 alleles in male gnomad4 subpopulation. Median coverage is 23. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.2634G>A	p.Arg878Arg	synonymous_variant	20/20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.2688G>A	p.Arg896Arg	synonymous_variant	22/22		NP_003579.3
CUL4B	NM_001330624.2	c.2649G>A	p.Arg883Arg	synonymous_variant	21/21		NP_001317553.1
CUL4B	NM_001369145.1	c.2100G>A	p.Arg700Arg	synonymous_variant	20/20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.2634G>A	p.Arg878Arg	synonymous_variant	20/20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.2748G>A	p.Arg916Arg	synonymous_variant	23/23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.2688G>A	p.Arg896Arg	synonymous_variant	22/22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.2688G>A	p.Arg896Arg	synonymous_variant	23/23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.2688G>A	p.Arg896Arg	synonymous_variant	25/25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.2649G>A	p.Arg883Arg	synonymous_variant	21/21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.2640G>A	p.Arg880Arg	synonymous_variant	20/20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.2541G>A	p.Arg847Arg	synonymous_variant	20/20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.2481G>A	p.Arg827Arg	synonymous_variant	19/19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.2289G>A	p.Arg763Arg	synonymous_variant	21/21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.2100G>A	p.Arg700Arg	synonymous_variant	20/20	5		ENSP00000360374.3
CUL4B	ENST00000679844.1	c.1971G>A	p.Arg657Arg	synonymous_variant	18/18			ENSP00000505239.1
CUL4B	ENST00000680474	c.*80G>A		3_prime_UTR_variant	20/20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*2081G>A		non_coding_transcript_exon_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*190G>A		non_coding_transcript_exon_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1843G>A		non_coding_transcript_exon_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1843G>A		non_coding_transcript_exon_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1550G>A		non_coding_transcript_exon_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1843G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*800G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3527G>A		non_coding_transcript_exon_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*806G>A		non_coding_transcript_exon_variant	20/20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*2081G>A		3_prime_UTR_variant	21/21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.*190G>A		3_prime_UTR_variant	18/18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*1843G>A		3_prime_UTR_variant	22/22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*1843G>A		3_prime_UTR_variant	22/22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*1550G>A		3_prime_UTR_variant	18/18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*1843G>A		3_prime_UTR_variant	20/20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.*800G>A		3_prime_UTR_variant	20/20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*3527G>A		3_prime_UTR_variant	17/17			ENSP00000505739.1
CUL4B	ENST00000681908.1	n.*806G>A		3_prime_UTR_variant	20/20			ENSP00000505777.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 399 AN: 111724 Hom.: 2 Cov.: 23 AF XY: 0.00254 AC XY: 86 AN XY: 33920

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000666

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: 0.00

Gnomad OTH AF: 0.00268

GnomAD3 exomes AF: 0.000908 AC: 166 AN: 182828 Hom.: 1 AF XY: 0.000445 AC XY: 30 AN XY: 67416

Gnomad AFR exome AF: 0.0117

Gnomad AMR exome AF: 0.000365

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000443

GnomAD4 exome AF: 0.000382 AC: 414 AN: 1083397 Hom.: 2 Cov.: 26 AF XY: 0.000268 AC XY: 94 AN XY: 350503

Gnomad4 AFR exome AF: 0.0137

Gnomad4 AMR exome AF: 0.000487

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000372

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000361

Gnomad4 OTH exome AF: 0.000794

GnomAD4 genome AF: 0.00359 AC: 401 AN: 111776 Hom.: 2 Cov.: 23 AF XY: 0.00256 AC XY: 87 AN XY: 33982

Gnomad4 AFR AF: 0.0127

Gnomad4 AMR AF: 0.000665

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00264

Alfa AF: 0.00204 Hom.: 6

Bravo AF: 0.00399

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 06, 2018

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 15, 2024

- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 09, 2017

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	5.0
DANN	Benign	0.55

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

Publications

LitVar

Other links and lift over

dbSNP: rs143580749; hg19: chrX-119660670;