13-113209674-G-A

Position:

• chr13-113209674-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001008895.4(CUL4A):​c.47G>A​(p.Gly16Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000302 in 993,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000030 (0 hom.)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.777

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35807067).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CUL4A	NM_001008895.4	c.47G>A	p.Gly16Asp	missense_variant	1/20	ENST00000375440.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CUL4A	ENST00000375440.9	c.47G>A	p.Gly16Asp	missense_variant	1/20	1	NM_001008895.4	P1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000302 AC: 3 AN: 993648 Hom.: 0 Cov.: 31 AF XY: 0.00000214 AC XY: 1 AN XY: 467470

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: 0.00000347

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 30

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

Feb 10, 2022

The c.47G>A (p.G16D) alteration is located in exon 1 (coding exon 1) of the CUL4A gene. This alteration results from a G to A substitution at nucleotide position 47, causing the glycine (G) at amino acid position 16 to be replaced by an aspartic acid (D). 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	0.27
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.33	T;.
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.77	T;T
M_CAP	Pathogenic	0.74	D
MetaRNN	Benign	0.36	T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	0.67	D;D;D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Benign	-1.6	N;.
REVEL	Uncertain	0.29
Sift	Uncertain	0.016	D;.
Sift4G	Benign	0.13	T;T
Polyphen		0.60	P;.
Vest4		0.17
MutPred		0.33		Gain of catalytic residue at R17 (P = 0.0013);Gain of catalytic residue at R17 (P = 0.0013);
MVP		0.76
MPC		0.90
ClinPred		0.35	T
GERP RS		2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.29

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr13-113863988;