dbSNP rs147136485: CUL4A:p.Thr180Ser (chr13-113233203-C-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001008895.4(CUL4A):c.539C>G(p.Thr180Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T180I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CUL4A
NM_001008895.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.55

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12460297).

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.539C>G	p.Thr180Ser	missense	Exon 6 of 20	NP_001008895.1	Q13619-1
CUL4A	NM_001278514.3		c.263C>G	p.Thr88Ser	missense	Exon 6 of 20	NP_001265443.1	A0A0A0MR50
CUL4A	NM_001278513.3		c.239C>G	p.Thr80Ser	missense	Exon 6 of 20	NP_001265442.1	Q13619-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CUL4A	ENST00000375440.9	TSL:1 MANE Select	c.539C>G	p.Thr180Ser	missense	Exon 6 of 20	ENSP00000364589.4	Q13619-1
CUL4A	ENST00000326335.8	TSL:1	c.263C>G	p.Thr88Ser	missense	Exon 6 of 20	ENSP00000322132.5	A0A0A0MR50
CUL4A	ENST00000375441.7	TSL:1	c.239C>G	p.Thr80Ser	missense	Exon 6 of 20	ENSP00000364590.3	Q13619-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461666

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.0000224

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111868

Other (OTH)

AF:

0.00

AC:

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.15

BayesDel_noAF

Benign

-0.46

CADD

Benign

8.2

(source)

DANN

Benign

0.31

DEOGEN2

Benign

0.0055

Eigen

Benign

-0.91

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.29

LIST_S2

Benign

0.46

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.93

MutationAssessor

Benign

-0.18

PhyloP100

1.6

PrimateAI

Benign

0.43

PROVEAN

Benign

0.42

REVEL

Benign

0.11

Sift

Benign

0.69

Sift4G

Benign

0.75

Polyphen

0.0

Vest4

0.30

MutPred

0.42

Gain of catalytic residue at R179 (P = 0)

MVP

0.36

MPC

0.36

ClinPred

0.042

GERP RS

1.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.045

gMVP

0.048

Mutation Taster

=90/10

polymorphism

(source)

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

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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