rs762094686

Positions:

• chrX-120545526-GA-G
• chrX-120545526-GA-GAA

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_001079872.2(CUL4B):​c.847-10del variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00103 in 1,096,758 control chromosomes in the GnomAD database, including 6 homozygotes. There are 268 hemizygotes in GnomAD. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0048 (2 hom., 135 hem., cov: 22)
  • Exomes 𝑓: 0.00062 (4 hom. 133 hem.)
• Consequence: CUL4B NM_001079872.2 splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.333

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 -16 ACMG points.

• BP6: Variant X-120545526-GA-G is Benign according to our data. Variant chrX-120545526-GA-G is described in ClinVar as [Likely_benign]. Clinvar id is 418559.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-120545526-GA-G is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00479 (520/108534) while in subpopulation AFR AF= 0.0163 (488/29872). AF 95% confidence interval is 0.0151. There are 2 homozygotes in gnomad4. There are 135 alleles in male gnomad4 subpopulation. Median coverage is 22. 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.847-10del		splice_polypyrimidine_tract_variant, intron_variant		ENST00000371322.11	NP_001073341.1
CUL4B	NM_001330624.2	c.862-10del		splice_polypyrimidine_tract_variant, intron_variant			NP_001317553.1
CUL4B	NM_001369145.1	c.313-10del		splice_polypyrimidine_tract_variant, intron_variant			NP_001356074.1
CUL4B	NM_003588.4	c.901-10del		splice_polypyrimidine_tract_variant, intron_variant			NP_003579.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.847-10del		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001079872.2	ENSP00000360373

Frequencies

GnomAD3 genomes AF: 0.00476 AC: 516 AN: 108490 Hom.: 2 Cov.: 22 AF XY: 0.00416 AC XY: 131 AN XY: 31510

Gnomad AFR AF: 0.0162

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00256

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: 0.00413

GnomAD3 exomes AF: 0.00146 AC: 165 AN: 112836 Hom.: 1 AF XY: 0.00109 AC XY: 38 AN XY: 34842

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.000718

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000789

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.000179

Gnomad OTH exome AF: 0.000989

GnomAD4 exome AF: 0.000622 AC: 615 AN: 988224 Hom.: 4 Cov.: 23 AF XY: 0.000463 AC XY: 133 AN XY: 286982

Gnomad4 AFR exome AF: 0.0175

Gnomad4 AMR exome AF: 0.00119

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000355

Gnomad4 SAS exome AF: 0.0000626

Gnomad4 FIN exome AF: 0.0000796

Gnomad4 NFE exome AF: 0.0000976

Gnomad4 OTH exome AF: 0.00176

GnomAD4 genome AF: 0.00479 AC: 520 AN: 108534 Hom.: 2 Cov.: 22 AF XY: 0.00428 AC XY: 135 AN XY: 31566

Gnomad4 AFR AF: 0.0163

Gnomad4 AMR AF: 0.00255

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: 0.00409

Alfa AF: 0.00118 Hom.: 4

Bravo AF: 0.00546

Asia WGS AF: 0.00239 AC: 6 AN: 2518

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 17, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 12, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 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. -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 16, 2014

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Jan 16, 2019

- -

Computational scores

Source: dbNSFP v4.3

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: rs762094686; hg19: chrX-119679381;