13-113233203-C-T

Variant names:

• chr13-113233203-C-T
• rs147136485
• NM_001008895.4:c.539C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001008895.4(CUL4A):​c.539C>T​(p.Thr180Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000694 in 1,613,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.03679225).
• BS2: High AC in GnomAd4 at 54 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001008895.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4A	NM_001008895.4	MANE Select	c.539C>T	p.Thr180Ile	missense	Exon 6 of 20	NP_001008895.1	Q13619-1
	CUL4A	NM_001278514.3		c.263C>T	p.Thr88Ile	missense	Exon 6 of 20	NP_001265443.1	A0A0A0MR50
	CUL4A	NM_001278513.3		c.239C>T	p.Thr80Ile	missense	Exon 6 of 20	NP_001265442.1	Q13619-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4A	ENST00000375440.9	TSL:1 MANE Select	c.539C>T	p.Thr180Ile	missense	Exon 6 of 20	ENSP00000364589.4	Q13619-1
	CUL4A	ENST00000326335.8	TSL:1	c.263C>T	p.Thr88Ile	missense	Exon 6 of 20	ENSP00000322132.5	A0A0A0MR50
	CUL4A	ENST00000375441.7	TSL:1	c.239C>T	p.Thr80Ile	missense	Exon 6 of 20	ENSP00000364590.3	Q13619-2

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 251202 AF XY: 0.000110

Gnomad AFR exome AF: 0.00135

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000397 AC: 58 AN: 1461666 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727132

African (AFR) AF: 0.00146 AC: 49 AN: 33478

American (AMR) AF: 0.0000671 AC: 3 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111868

Other (OTH) AF: 0.0000994 AC: 6 AN: 60380

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000416 AC XY: 31 AN XY: 74480

African (AFR) AF: 0.00115 AC: 48 AN: 41570

American (AMR) AF: 0.000327 AC: 5 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000329 Hom.: 0

Bravo AF: 0.000329

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000132 AC: 16

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.67	T
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.037	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.6
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.17
Sift	Benign	0.22	T
Sift4G	Benign	0.20	T
Polyphen		0.0	B
Vest4		0.38
MVP		0.46
MPC		0.43
ClinPred		0.0060	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.056
gMVP		0.14
Mutation Taster		=85/15	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: rs147136485; hg19: chr13-113887517;