13-113233931-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001008895.4(CUL4A):c.710A>G(p.Glu237Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.74

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL4A	NM_001008895.4	c.710A>G	p.Glu237Gly	missense_variant	7/20	ENST00000375440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL4A	ENST00000375440.9	c.710A>G	p.Glu237Gly	missense_variant	7/20	1	NM_001008895.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458402 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 725760

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

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

Dec 13, 2022

The c.710A>G (p.E237G) alteration is located in exon 7 (coding exon 7) of the CUL4A gene. This alteration results from a A to G substitution at nucleotide position 710, causing the glutamic acid (E) at amino acid position 237 to be replaced by a glycine (G). 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	0.17
BayesDel_addAF	Uncertain	0.074	D
BayesDel_noAF	Benign	-0.13
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.050
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.40	T;T;T;T;T
MetaSVM	Uncertain	0.016	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D;.;D;.;D
REVEL	Uncertain	0.44
Sift	Benign	0.036	D;.;D;.;D
Sift4G	Uncertain	0.060	T;T;T;T;T
Polyphen		0.026	.;.;.;.;B
Vest4		0.42
MutPred		0.55		.;.;.;.;Gain of catalytic residue at L242 (P = 8e-04);
MVP		0.81
MPC		0.57
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.43
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.31		Position offset: -34

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-113888245;