13-113209652-G-T

Variant names:

• chr13-113209652-G-T
• rs1223236804
• NM_001008895.4:c.25G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001008895.4(CUL4A):​c.25G>T​(p.Gly9Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000179 in 1,120,194 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000068 (0 hom., cov: 30)
  • Exomes 𝑓: 0.0000010 (0 hom.)
• Consequence: CUL4A NM_001008895.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.60
• 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: Uncertain_significance. The variant received 2 ACMG points.

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

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.25G>T	p.Gly9Cys	missense	Exon 1 of 20	NP_001008895.1	Q13619-1
	CUL4A	NM_001354943.2		c.25G>T	p.Gly9Cys	missense	Exon 1 of 6	NP_001341872.1	A0A087WWN2
	CUL4A	NM_001354940.2		c.-251G>T		5_prime_UTR	Exon 1 of 20	NP_001341869.1	Q13619-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL4A	ENST00000375440.9	TSL:1 MANE Select	c.25G>T	p.Gly9Cys	missense	Exon 1 of 20	ENSP00000364589.4	Q13619-1
	CUL4A	ENST00000326335.8	TSL:1	c.-152-321G>T		intron	N/A	ENSP00000322132.5	A0A0A0MR50
	CUL4A	ENST00000375441.7	TSL:1	c.-152-321G>T		intron	N/A	ENSP00000364590.3	Q13619-2

Frequencies

GnomAD3 genomes AF: 0.00000675 AC: 1 AN: 148040 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000668

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: 0.00

GnomAD4 exome AF: 0.00000103 AC: 1 AN: 972154 Hom.: 0 Cov.: 31 AF XY: 0.00000219 AC XY: 1 AN XY: 456772

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 19106

American (AMR) AF: 0.00 AC: 0 AN: 4972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 9746

East Asian (EAS) AF: 0.00 AC: 0 AN: 16368

South Asian (SAS) AF: 0.0000539 AC: 1 AN: 18546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 13940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2348

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 851222

Other (OTH) AF: 0.00 AC: 0 AN: 35906

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000675 AC: 1 AN: 148040 Hom.: 0 Cov.: 30 AF XY: 0.0000139 AC XY: 1 AN XY: 72126

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 40888

American (AMR) AF: 0.0000668 AC: 1 AN: 14962

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 4986

South Asian (SAS) AF: 0.00 AC: 0 AN: 4800

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66544

Other (OTH) AF: 0.00 AC: 0 AN: 2048

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

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	0.20
BayesDel_addAF	Benign	-0.045	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.0061
Eigen_PC	Benign	0.025
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.71	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.6	L
PhyloP100		1.6
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.67	N
REVEL	Benign	0.20
Sift	Benign	0.038	D
Sift4G	Benign	0.074	T
Polyphen		0.51	P
Vest4		0.32
MutPred		0.40		Loss of relative solvent accessibility (P = 0.008)
MVP		0.76
MPC		0.66
ClinPred		0.59	D
GERP RS		4.0
PromoterAI		0.23	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.14
gMVP		0.31
Mutation Taster		=94/6	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: rs1223236804; hg19: chr13-113863966;