X-120560500-T-G

Variant names:

• chrX-120560500-T-G
• rs145134351
• NM_001079872.2:c.139A>C

Variant summary

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

The NM_001079872.2(CUL4B):​c.139A>C​(p.Ser47Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. S47G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 22)
• Consequence: CUL4B NM_001079872.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.26
• Publications: 2 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=0.33502778).

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.139A>C	p.Ser47Arg	missense	Exon 1 of 20	NP_001073341.1
	CUL4B	NM_003588.4		c.193A>C	p.Ser65Arg	missense	Exon 3 of 22	NP_003579.3
	CUL4B	NM_001330624.2		c.154A>C	p.Ser52Arg	missense	Exon 2 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.139A>C	p.Ser47Arg	missense	Exon 1 of 20	ENSP00000360373.5
	CUL4B	ENST00000681206.1		c.154A>C	p.Ser52Arg	missense	Exon 2 of 23	ENSP00000505480.1
	CUL4B	ENST00000680673.1		c.193A>C	p.Ser65Arg	missense	Exon 3 of 22	ENSP00000505084.1

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.14	N
REVEL	Benign	0.24
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.35
MutPred		0.38		Loss of phosphorylation at S65 (P = 4e-04)
MVP		0.83
MPC		1.0
ClinPred		0.71	D
GERP RS		5.4
PromoterAI		0.033	Neutral
Varity_R		0.35
gMVP		0.38
Mutation Taster		=97/3	polymorphism

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: rs145134351; hg19: chrX-119694355;