rs757649304

Variant names:

• chrX-120542981-C-T
• rs757649304
• NM_001079872.2:c.1309G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001079872.2(CUL4B):​c.1309G>A​(p.Ala437Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000369 in 1,084,033 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 22)
  • Exomes 𝑓: 0.0000037 (0 hom. 1 hem.)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 6.06
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28231257).

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.1309G>A	p.Ala437Thr	missense	Exon 9 of 20	NP_001073341.1
	CUL4B	NM_003588.4		c.1363G>A	p.Ala455Thr	missense	Exon 11 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.1324G>A	p.Ala442Thr	missense	Exon 10 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.1309G>A	p.Ala437Thr	missense	Exon 9 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.1423G>A	p.Ala475Thr	missense	Exon 12 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.1363G>A	p.Ala455Thr	missense	Exon 11 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD2 exomes AF: 0.0000223 AC: 4 AN: 179477 AF XY: 0.0000155

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000743

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000369 AC: 4 AN: 1084033 Hom.: 0 Cov.: 25 AF XY: 0.00000285 AC XY: 1 AN XY: 350737

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

African (AFR) AF: 0.00 AC: 0 AN: 26114

American (AMR) AF: 0.0000571 AC: 2 AN: 35009

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19197

East Asian (EAS) AF: 0.00 AC: 0 AN: 30039

South Asian (SAS) AF: 0.00 AC: 0 AN: 53226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4038

European-Non Finnish (NFE) AF: 0.00000241 AC: 2 AN: 830402

Other (OTH) AF: 0.00 AC: 0 AN: 45608

⚠️ 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

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	X-linked intellectual disability Cabezas type (2)
-	1	-	Inborn genetic diseases (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.053	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.20	T
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.86	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.26	N
PhyloP100		6.1
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.21
Sift	Benign	0.50	T
Sift4G	Benign	0.52	T
Polyphen		0.090	B
Vest4		0.50
MutPred		0.45		Gain of ubiquitination at K459 (P = 0.0882)
MVP		0.93
MPC		0.62
ClinPred		0.16	T
GERP RS		5.6
Varity_R		0.63
gMVP		0.58
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs757649304; hg19: chrX-119676836;