Genetic Variant CUL4A:p.Arg49Gln (chr13-113209773-G-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001008895.4(CUL4A):c.146G>A(p.Arg49Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CUL4A
NM_001008895.4 missense, splice_region

Scores

Splicing: ADA: 0.00001490

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.903

Publications

0 publications found

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.26866555).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL4A	NM_001008895.4	MANE Select	c.146G>A	p.Arg49Gln	missense splice_region	Exon 1 of 20	NP_001008895.1	Q13619-1
CUL4A	NM_001354940.2		c.-130G>A		splice_region	Exon 1 of 20	NP_001341869.1	Q13619-2
CUL4A	NM_001354941.2		c.-288G>A		splice_region	Exon 1 of 20	NP_001341870.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL4A	ENST00000375440.9	TSL:1 MANE Select	c.146G>A	p.Arg49Gln	missense splice_region	Exon 1 of 20	ENSP00000364589.4	Q13619-1
CUL4A	ENST00000326335.8	TSL:1	c.-152-200G>A		intron	N/A	ENSP00000322132.5	A0A0A0MR50
CUL4A	ENST00000375441.7	TSL:1	c.-152-200G>A		intron	N/A	ENSP00000364590.3	Q13619-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1028836

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

486638

African (AFR)

AF:

0.00

AC:

AN:

21420

American (AMR)

AF:

0.00

AC:

AN:

6874

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

11374

East Asian (EAS)

AF:

0.00

AC:

AN:

22310

South Asian (SAS)

AF:

0.00

AC:

AN:

19854

European-Finnish (FIN)

AF:

0.00

AC:

AN:

18384

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2602

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

886762

Other (OTH)

AF:

0.00

AC:

AN:

39256

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.41

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Benign

-0.29

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.82

M_CAP

Pathogenic

0.73

MetaRNN

Benign

0.27

MetaSVM

Benign

-0.86

MutationAssessor

Uncertain

2.1

PhyloP100

0.90

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-0.95

REVEL

Benign

0.17

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.014

Polyphen

0.82

Vest4

0.19

MutPred

0.43

Gain of catalytic residue at R53 (P = 0.0044)

MVP

0.78

MPC

0.49

ClinPred

0.59

GERP RS

2.1

PromoterAI

0.010

Neutral

(source)

Varity_R

0.28

gMVP

0.31

Mutation Taster

=86/14

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000015

dbscSNV1_RF

Benign

0.032

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over