rs1556213268

Variant names:

• chrX-120544181-T-A
• rs1556213268
• NM_001079872.2:c.1106A>T

Your query was ambiguous. Multiple possible variants found:

• chrX-120544181-T-A
• chrX-120544181-T-C

Variant summary

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

The NM_001079872.2(CUL4B):​c.1106A>T​(p.Gln369Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000092 in 1,087,361 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q369R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.2e-7 (0 hom. 0 hem.)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.95
• 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

LOC124905273 (HGNC:):

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_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.1106A>T	p.Gln369Leu	missense	Exon 7 of 20	NP_001073341.1
	CUL4B	NM_003588.4		c.1160A>T	p.Gln387Leu	missense	Exon 9 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.1121A>T	p.Gln374Leu	missense	Exon 8 of 21	NP_001317553.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4B	ENST00000371322.11	TSL:1 MANE Select	c.1106A>T	p.Gln369Leu	missense	Exon 7 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.1220A>T	p.Gln407Leu	missense	Exon 10 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.1160A>T	p.Gln387Leu	missense	Exon 9 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.20e-7 AC: 1 AN: 1087361 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 353421

African (AFR) AF: 0.00 AC: 0 AN: 26197

American (AMR) AF: 0.00 AC: 0 AN: 35163

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19299

East Asian (EAS) AF: 0.00 AC: 0 AN: 30084

South Asian (SAS) AF: 0.00 AC: 0 AN: 53806

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40425

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4076

European-Non Finnish (NFE) AF: 0.00000120 AC: 1 AN: 832588

Other (OTH) AF: 0.00 AC: 0 AN: 45723

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	0.00042	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.50	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.52	D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.48	N
PhyloP100		8.0
PrimateAI	Uncertain	0.70	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.33
Sift	Benign	0.24	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.41
MutPred		0.40		Loss of disorder (P = 0.0377)
MVP		0.94
MPC		0.62
ClinPred		0.88	D
GERP RS		5.7
Varity_R		0.68
gMVP		0.85
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs1556213268; hg19: chrX-119678036;