13-113233206-A-G

Position:

• chr13-113233206-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001008895.4(CUL4A):​c.542A>G​(p.His181Arg) variant causes a missense change involving the alteration of a conserved nucleotide. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.03

Genes affected

CUL4A (HGNC:2554): (cullin 4A) CUL4A is the ubiquitin ligase component of a multimeric complex involved in the degradation of DNA damage-response proteins (Liu et al., 2009 [PubMed 19481525]).[supplied by OMIM, Oct 2009]

CUL4A (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.886

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CUL4A	NM_001008895.4	c.542A>G	p.His181Arg	missense_variant	6/20	ENST00000375440.9	NP_001008895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CUL4A	ENST00000375440.9	c.542A>G	p.His181Arg	missense_variant	6/20	1	NM_001008895.4	ENSP00000364589.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2024

The c.542A>G (p.H181R) alteration is located in exon 6 (coding exon 6) of the CUL4A gene. This alteration results from a A to G substitution at nucleotide position 542, causing the histidine (H) at amino acid position 181 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.076	.;T;.;.;T
Eigen	Benign	0.091
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	.;D;D;.;D
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.9	.;.;.;.;L
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-5.6	D;.;D;.;D
REVEL	Uncertain	0.63
Sift	Uncertain	0.010	D;.;D;.;D
Sift4G	Benign	0.22	T;T;T;T;T
Polyphen		0.091	.;.;.;.;B
Vest4		0.90
MutPred		0.60		.;.;.;.;Gain of catalytic residue at R179 (P = 0.0034);
MVP		0.95
MPC		0.54
ClinPred		0.98	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.69
gMVP		0.69

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

Publications

LitVar

Other links and lift over

dbSNP: rs2041419464; hg19: chr13-113887520; COSMIC: COSV100417442; COSMIC: COSV100417442;