chrX-120544179-G-A

Variant names:

• chrX-120544179-G-A
• rs121434616
• NM_001079872.2:c.1108C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001079872.2(CUL4B):​c.1108C>T​(p.Arg370*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CUL4B NM_001079872.2 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 4.75
• Publications: 11 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

LOC124905273 (HGNC:):

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant X-120544179-G-A is Pathogenic according to our data. Variant chrX-120544179-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 11339.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1108C>T	p.Arg370*	stop_gained	Exon 7 of 20	ENST00000371322.11	NP_001073341.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1108C>T	p.Arg370*	stop_gained	Exon 7 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1222C>T	p.Arg408*	stop_gained	Exon 10 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1162C>T	p.Arg388*	stop_gained	Exon 9 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1162C>T	p.Arg388*	stop_gained	Exon 10 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1162C>T	p.Arg388*	stop_gained	Exon 12 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1123C>T	p.Arg375*	stop_gained	Exon 8 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1108C>T	p.Arg370*	stop_gained	Exon 7 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1015C>T	p.Arg339*	stop_gained	Exon 7 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1108C>T	p.Arg370*	stop_gained	Exon 7 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.763C>T	p.Arg255*	stop_gained	Exon 8 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.574C>T	p.Arg192*	stop_gained	Exon 7 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.550C>T	p.Arg184*	stop_gained	Exon 6 of 20			ENSP00000505562.1
CUL4B	ENST00000679844.1	c.550C>T	p.Arg184*	stop_gained	Exon 6 of 18			ENSP00000505239.1
CUL4B	ENST00000673919.1	n.*555C>T		non_coding_transcript_exon_variant	Exon 8 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.550C>T		non_coding_transcript_exon_variant	Exon 6 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*317C>T		non_coding_transcript_exon_variant	Exon 9 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*317C>T		non_coding_transcript_exon_variant	Exon 9 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*24C>T		non_coding_transcript_exon_variant	Exon 5 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*317C>T		non_coding_transcript_exon_variant	Exon 7 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.550C>T		non_coding_transcript_exon_variant	Exon 6 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.1108C>T		non_coding_transcript_exon_variant	Exon 7 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.550C>T		non_coding_transcript_exon_variant	Exon 6 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.550C>T		non_coding_transcript_exon_variant	Exon 6 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*555C>T		3_prime_UTR_variant	Exon 8 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*317C>T		3_prime_UTR_variant	Exon 9 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*317C>T		3_prime_UTR_variant	Exon 9 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*24C>T		3_prime_UTR_variant	Exon 5 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*317C>T		3_prime_UTR_variant	Exon 7 of 20			ENSP00000505898.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

X-linked intellectual disability Cabezas type Pathogenic:2

Feb 01, 2024

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2007

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:2

Apr 26, 2018

Molecular Genetics laboratory, Necker Hospital

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Mar 04, 2025

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Seizure;C0349588:Short stature;C0424503:Abnormal facial shape;C0557874:Global developmental delay;C3714756:Intellectual disability Pathogenic:1

Nov 29, 2014

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.67	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	36
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		4.7
Vest4		0.83
GERP RS		3.8
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs121434616; hg19: chrX-119678034;