rs61743561

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_015089.4(CUL9):c.845G>A(p.Gly282Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,214 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G282R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.015 ( 25 hom., cov: 32)

Exomes 𝑓: 0.021 ( 430 hom. )

Consequence

CUL9
NM_015089.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.92

Publications

12 publications found

Variant links:

Genes affected

CUL9 (HGNC:15982): (cullin 9) Predicted to enable several functions, including ATP binding activity; metal ion binding activity; and ubiquitin protein ligase binding activity. Involved in microtubule cytoskeleton organization; protein ubiquitination; and regulation of mitotic nuclear division. Located in cytosol. Part of cullin-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

CUL9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0033248365).

BP6

Variant 6-43186049-G-A is Benign according to our data. Variant chr6-43186049-G-A is described in ClinVar as [Benign]. Clinvar id is 3056976.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2280/152326) while in subpopulation NFE AF = 0.024 (1631/68018). AF 95% confidence interval is 0.023. There are 25 homozygotes in GnomAd4. There are 1032 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4 link	c.845G>A	p.Gly282Glu	missense_variant	Exon 4 of 41	ENST00000252050.9	NP_055904.1	Q8IWT3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL9	ENST00000252050.9 link	c.845G>A	p.Gly282Glu	missense_variant	Exon 4 of 41	5	NM_015089.4	ENSP00000252050.4	Q8IWT3-1
CUL9	ENST00000372647.6 link	c.845G>A	p.Gly282Glu	missense_variant	Exon 4 of 41	1		ENSP00000361730.2	E9PEZ1
CUL9	ENST00000451399.5 link	n.920G>A		non_coding_transcript_exon_variant	Exon 4 of 5	2
CUL9	ENST00000515773.5 link	n.920G>A		non_coding_transcript_exon_variant	Exon 4 of 40	2

Frequencies

GnomAD3 genomes

AF:

0.0150

AC:

2281

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00441

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0158

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0124

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0240

Gnomad OTH

AF:

0.0163

GnomAD2 exomes

AF:

0.0149

AC:

3753

AN:

251442

AF XY:

0.0162

show subpopulations

Gnomad AFR exome

AF:

0.00369

Gnomad AMR exome

AF:

0.00830

Gnomad ASJ exome

AF:

0.000298

Gnomad EAS exome

AF:

0.000163

Gnomad FIN exome

AF:

0.0134

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0144

GnomAD4 exome

AF:

0.0211

AC:

30919

AN:

1461888

Hom.:

430

Cov.:

AF XY:

0.0210

AC XY:

15255

AN XY:

727246

show subpopulations

African (AFR)

AF:

0.00338

AC:

113

AN:

33480

American (AMR)

AF:

0.00910

AC:

407

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000230

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0134

AC:

1157

AN:

86258

European-Finnish (FIN)

AF:

0.0138

AC:

737

AN:

53416

Middle Eastern (MID)

AF:

0.00173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0247

AC:

27446

AN:

1112010

Other (OTH)

AF:

0.0172

AC:

1040

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

1972

3943

5915

7886

9858

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1036

2072

3108

4144

5180

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0150

AC:

2280

AN:

152326

Hom.:

Cov.:

AF XY:

0.0139

AC XY:

1032

AN XY:

74490

show subpopulations

African (AFR)

AF:

0.00440

AC:

183

AN:

41574

American (AMR)

AF:

0.0157

AC:

240

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0124

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0122

AC:

129

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0240

AC:

1631

AN:

68018

Other (OTH)

AF:

0.0161

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0193

Hom.:

101

Bravo

AF:

0.0139

TwinsUK

AF:

0.0229

AC:

ALSPAC

AF:

0.0239

AC:

ESP6500AA

AF:

0.00386

AC:

ESP6500EA

AF:

0.0236

AC:

203

ExAC

AF:

0.0144

AC:

1752

Asia WGS

AF:

0.00606

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CUL9-related disorder

Benign:1

Feb 19, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.37

CADD

Benign

(source)

DANN

Benign

0.72

DEOGEN2

Benign

0.060

T;T

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.61

T;T

MetaRNN

Benign

0.0033

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.84

L;.

PhyloP100

3.9

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.040

N;N

REVEL

Benign

0.072

Sift

Benign

0.18

T;T

Sift4G

Benign

0.93

T;T

Polyphen

0.0030

B;B

Vest4

0.066

MPC

0.96

ClinPred

0.013

GERP RS

4.4

Varity_R

0.034

gMVP

0.25

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over