Genetic Variant NM_001008895.4:c.575C>T (chr13-113233239-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001008895.4(CUL4A):c.575C>T(p.Thr192Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CUL4A
NM_001008895.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.99

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 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.762

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.575C>T	p.Thr192Ile	missense	Exon 6 of 20	NP_001008895.1	Q13619-1
CUL4A	NM_001278514.3		c.299C>T	p.Thr100Ile	missense	Exon 6 of 20	NP_001265443.1	A0A0A0MR50
CUL4A	NM_001278513.3		c.275C>T	p.Thr92Ile	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.575C>T	p.Thr192Ile	missense	Exon 6 of 20	ENSP00000364589.4	Q13619-1
CUL4A	ENST00000326335.8	TSL:1	c.299C>T	p.Thr100Ile	missense	Exon 6 of 20	ENSP00000322132.5	A0A0A0MR50
CUL4A	ENST00000375441.7	TSL:1	c.275C>T	p.Thr92Ile	missense	Exon 6 of 20	ENSP00000364590.3	Q13619-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461758

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33478

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53356

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

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

Benign

0.34

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Uncertain

-0.080

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.070

Eigen

Benign

-0.25

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.89

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.76

MetaSVM

Benign

-0.56

MutationAssessor

Benign

0.84

PhyloP100

6.0

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-4.8

REVEL

Uncertain

0.42

Sift

Benign

0.30

Sift4G

Benign

0.52

Polyphen

0.011

Vest4

0.83

MutPred

0.48

Gain of catalytic residue at M187 (P = 0)

MVP

0.79

MPC

0.52

ClinPred

0.88

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.64

gMVP

0.38

Mutation Taster

=41/59

disease causing

(source)

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

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