NM_001079872.2:c.847-2A>G

Variant names:

• chrX-120545519-T-C
• rs786200913
• NM_001079872.2:c.847-2A>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001079872.2(CUL4B):​c.847-2A>G variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CUL4B NM_001079872.2 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.99
• Publications: 1 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: Pathogenic. The variant received 11 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, Cryptic splice site detected, with MaxEntScore 7.8, offset of 35, new splice context is: atttttttgtttctggatAGaac. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120545519-T-C is Pathogenic according to our data. Variant chrX-120545519-T-C is described in ClinVar as Pathogenic. ClinVar VariationId is 11340.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001079872.2. 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.847-2A>G		splice_acceptor intron	N/A	NP_001073341.1
	CUL4B	NM_003588.4		c.901-2A>G		splice_acceptor intron	N/A	NP_003579.3
	CUL4B	NM_001330624.2		c.862-2A>G		splice_acceptor 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.847-2A>G		splice_acceptor intron	N/A	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.961-2A>G		splice_acceptor intron	N/A	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.901-2A>G		splice_acceptor intron	N/A	ENSP00000505084.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1037234 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 320716

African (AFR) AF: 0.00 AC: 0 AN: 25357

American (AMR) AF: 0.00 AC: 0 AN: 30364

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18580

East Asian (EAS) AF: 0.00 AC: 0 AN: 29062

South Asian (SAS) AF: 0.00 AC: 0 AN: 49901

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3980

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 797846

Other (OTH) AF: 0.00 AC: 0 AN: 43902

GnomAD4 genome Cov.: 22

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:1

Feb 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
PhyloP100		8.0
GERP RS		5.7
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.99		Position offset: -2

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

Other links and lift over

dbSNP: rs786200913; hg19: chrX-119679374;