X-120545526-GA-GAAA

Variant names:

• chrX-120545526-G-GAA
• rs762094686
• NM_001079872.2:c.847-11_847-10dupTT

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003588.4(CUL4B):​c.901-11_901-10dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000101 in 989,825 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000010 (0 hom. 0 hem.)
• Consequence: CUL4B NM_003588.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.333
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• X-linked intellectual disability, Cabezas type

  Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, G2P

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003588.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	NM_001079872.2	MANE Select	c.847-11_847-10dupTT		intron	N/A	NP_001073341.1
	CUL4B	NM_003588.4		c.901-11_901-10dupTT		intron	N/A	NP_003579.3
	CUL4B	NM_001330624.2		c.862-11_862-10dupTT		intron	N/A	NP_001317553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.847-10_847-9insTT		intron	N/A	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.961-10_961-9insTT		intron	N/A	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.901-10_901-9insTT		intron	N/A	ENSP00000505084.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome AF: 0.00000101 AC: 1 AN: 989825 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 288071

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000416 AC: 1 AN: 24056

American (AMR) AF: 0.00 AC: 0 AN: 28665

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18000

East Asian (EAS) AF: 0.00 AC: 0 AN: 28238

South Asian (SAS) AF: 0.00 AC: 0 AN: 47976

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3804

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 759306

Other (OTH) AF: 0.00 AC: 0 AN: 42088

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 22

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.33

Splicing

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

Other links and lift over

dbSNP: rs762094686; hg19: chrX-119679381;