rs121434615

Variant names:

• chrX-120539349-G-A
• rs121434615
• NM_001079872.2:c.1660C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001079872.2(CUL4B):​c.1660C>T​(p.Arg554Cys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 12/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0 (0 hom. 0 hem.)
  • Failed GnomAD Quality Control
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 6.29
• Publications: 7 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.988
• PP5: Variant X-120539349-G-A is Pathogenic according to our data. Variant chrX-120539349-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 11338.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL4B	NM_001079872.2	c.1660C>T	p.Arg554Cys	missense_variant	Exon 12 of 20	ENST00000371322.11	NP_001073341.1
CUL4B	NM_003588.4	c.1714C>T	p.Arg572Cys	missense_variant	Exon 14 of 22		NP_003579.3
CUL4B	NM_001330624.2	c.1675C>T	p.Arg559Cys	missense_variant	Exon 13 of 21		NP_001317553.1
CUL4B	NM_001369145.1	c.1126C>T	p.Arg376Cys	missense_variant	Exon 12 of 20		NP_001356074.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL4B	ENST00000371322.11	c.1660C>T	p.Arg554Cys	missense_variant	Exon 12 of 20	1	NM_001079872.2	ENSP00000360373.5
CUL4B	ENST00000681206.1	c.1774C>T	p.Arg592Cys	missense_variant	Exon 15 of 23			ENSP00000505480.1
CUL4B	ENST00000680673.1	c.1714C>T	p.Arg572Cys	missense_variant	Exon 14 of 22			ENSP00000505084.1
CUL4B	ENST00000681253.1	c.1714C>T	p.Arg572Cys	missense_variant	Exon 15 of 23			ENSP00000506259.1
CUL4B	ENST00000681652.1	c.1714C>T	p.Arg572Cys	missense_variant	Exon 17 of 25			ENSP00000505176.1
CUL4B	ENST00000336592.11	c.1675C>T	p.Arg559Cys	missense_variant	Exon 13 of 21	5		ENSP00000338919.6
CUL4B	ENST00000674137.11	c.1660C>T	p.Arg554Cys	missense_variant	Exon 12 of 20			ENSP00000501019.6
CUL4B	ENST00000681090.1	c.1567C>T	p.Arg523Cys	missense_variant	Exon 12 of 20			ENSP00000506288.1
CUL4B	ENST00000404115.8	c.1660C>T	p.Arg554Cys	missense_variant	Exon 12 of 19	1		ENSP00000384109.4
CUL4B	ENST00000679927.1	c.1315C>T	p.Arg439Cys	missense_variant	Exon 13 of 21			ENSP00000505603.1
CUL4B	ENST00000371323.3	c.1126C>T	p.Arg376Cys	missense_variant	Exon 12 of 20	5		ENSP00000360374.3
CUL4B	ENST00000680474.1	c.1102C>T	p.Arg368Cys	missense_variant	Exon 11 of 20			ENSP00000505562.1
CUL4B	ENST00000673919.1	n.*1107C>T		non_coding_transcript_exon_variant	Exon 13 of 21			ENSP00000500994.1
CUL4B	ENST00000674073.2	n.1102C>T		non_coding_transcript_exon_variant	Exon 11 of 18			ENSP00000501262.2
CUL4B	ENST00000679405.1	n.*869C>T		non_coding_transcript_exon_variant	Exon 14 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*869C>T		non_coding_transcript_exon_variant	Exon 14 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*576C>T		non_coding_transcript_exon_variant	Exon 10 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*869C>T		non_coding_transcript_exon_variant	Exon 12 of 20			ENSP00000505898.1
CUL4B	ENST00000681189.1	n.1102C>T		non_coding_transcript_exon_variant	Exon 11 of 20			ENSP00000505973.1
CUL4B	ENST00000681333.1	n.*1606C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000681869.1	n.1102C>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000505597.1
CUL4B	ENST00000681908.1	n.1102C>T		non_coding_transcript_exon_variant	Exon 11 of 20			ENSP00000505777.1
CUL4B	ENST00000673919.1	n.*1107C>T		3_prime_UTR_variant	Exon 13 of 21			ENSP00000500994.1
CUL4B	ENST00000679405.1	n.*869C>T		3_prime_UTR_variant	Exon 14 of 22			ENSP00000504985.1
CUL4B	ENST00000679432.1	n.*869C>T		3_prime_UTR_variant	Exon 14 of 22			ENSP00000505343.1
CUL4B	ENST00000680918.1	n.*576C>T		3_prime_UTR_variant	Exon 10 of 18			ENSP00000505955.1
CUL4B	ENST00000681080.1	n.*869C>T		3_prime_UTR_variant	Exon 12 of 20			ENSP00000505898.1
CUL4B	ENST00000681333.1	n.*1606C>T		3_prime_UTR_variant	Exon 11 of 17			ENSP00000505739.1
CUL4B	ENST00000679844.1	c.1079-579C>T		intron_variant	Intron 10 of 17			ENSP00000505239.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 1078117 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 345055

African (AFR) AF: 0.00 AC: 0 AN: 26008

American (AMR) AF: 0.00 AC: 0 AN: 34583

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19135

East Asian (EAS) AF: 0.00 AC: 0 AN: 30029

South Asian (SAS) AF: 0.00 AC: 0 AN: 52454

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40173

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4084

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 826314

Other (OTH) AF: 0.00 AC: 0 AN: 45337

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

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

- -

not provided Pathogenic:1

Mar 07, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 23348097, 20064923, 19377476, 17236139, 28454995, 21816345) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.76	.;.;D
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Pathogenic	0.97	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.80	D
MutationAssessor	Pathogenic	3.7	.;.;H
PhyloP100		6.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-7.7	D;D;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.80
MutPred		0.91		.;.;Loss of MoRF binding (P = 0.0249);
MVP		0.99
MPC		3.5
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.97
gMVP		0.88
Mutation Taster		=9/91	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121434615; hg19: chrX-119673204; COSMIC: COSV105205898; COSMIC: COSV105205898;