rs3738952

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_003590.5(CUL3):c.1699G>A(p.Val567Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.104 in 1,609,540 control chromosomes in the GnomAD database, including 10,865 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.091 ( 877 hom., cov: 32)

Exomes 𝑓: 0.11 ( 9988 hom. )

Consequence

CUL3
NM_003590.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.69

Publications

40 publications found

Variant links:

Genes affected

CUL3 (HGNC:2553): (cullin 3) This gene encodes a member of the cullin protein family. The encoded protein plays a critical role in the polyubiquitination and subsequent degradation of specific protein substrates as the core component and scaffold protein of an E3 ubiquitin ligase complex. Complexes including the encoded protein may also play a role in late endosome maturation. Mutations in this gene are a cause of type 2E pseudohypoaldosteronism. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

CUL3 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
neurodevelopmental disorder with or without autism or seizures
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
pseudohypoaldosteronism type 2E
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics, ClinGen

CUL3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001349926).

BP6

Variant 2-224497761-C-T is Benign according to our data. Variant chr2-224497761-C-T is described in ClinVar as Benign. ClinVar VariationId is 259091.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.255 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5 link	c.1699G>A	p.Val567Ile	missense_variant	Exon 12 of 16	ENST00000264414.9	NP_003581.1	Q13618-1A0A024R475

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL3	ENST00000264414.9 link	c.1699G>A	p.Val567Ile	missense_variant	Exon 12 of 16	1	NM_003590.5	ENSP00000264414.4		Q13618-1

Frequencies

GnomAD3 genomes

AF:

0.0906

AC:

13772

AN:

152070

Hom.:

878

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0276

Gnomad AMI

AF:

0.104

Gnomad AMR

AF:

0.166

Gnomad ASJ

AF:

0.0631

Gnomad EAS

AF:

0.266

Gnomad SAS

AF:

0.202

Gnomad FIN

AF:

0.0950

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0910

Gnomad OTH

AF:

0.103

GnomAD2 exomes

AF:

0.131

AC:

32960

AN:

250984

AF XY:

0.131

show subpopulations

Gnomad AFR exome

AF:

0.0255

Gnomad AMR exome

AF:

0.212

Gnomad ASJ exome

AF:

0.0641

Gnomad EAS exome

AF:

0.270

Gnomad FIN exome

AF:

0.0971

Gnomad NFE exome

AF:

0.0950

Gnomad OTH exome

AF:

0.127

GnomAD4 exome

AF:

0.105

AC:

153367

AN:

1457352

Hom.:

9988

Cov.:

AF XY:

0.107

AC XY:

77881

AN XY:

725306

show subpopulations

African (AFR)

AF:

0.0227

AC:

757

AN:

33398

American (AMR)

AF:

0.205

AC:

9167

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.0654

AC:

1706

AN:

26098

East Asian (EAS)

AF:

0.290

AC:

11475

AN:

39634

South Asian (SAS)

AF:

0.187

AC:

16132

AN:

86086

European-Finnish (FIN)

AF:

0.102

AC:

5435

AN:

53372

Middle Eastern (MID)

AF:

0.100

AC:

579

AN:

5762

European-Non Finnish (NFE)

AF:

0.0915

AC:

101396

AN:

1108080

Other (OTH)

AF:

0.112

AC:

6720

AN:

60220

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.469

Heterozygous variant carriers

5776

11552

17328

23104

28880

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3930

7860

11790

15720

19650

<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:

0.0905

AC:

13778

AN:

152188

Hom.:

877

Cov.:

AF XY:

0.0936

AC XY:

6964

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.0276

AC:

1146

AN:

41536

American (AMR)

AF:

0.166

AC:

2537

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0631

AC:

219

AN:

3472

East Asian (EAS)

AF:

0.266

AC:

1380

AN:

5182

South Asian (SAS)

AF:

0.202

AC:

974

AN:

4814

European-Finnish (FIN)

AF:

0.0950

AC:

1006

AN:

10590

Middle Eastern (MID)

AF:

0.0714

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0910

AC:

6187

AN:

67996

Other (OTH)

AF:

0.101

AC:

213

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

599

1199

1798

2398

2997

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<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:

0.0959

Hom.:

3733

Bravo

AF:

0.0941

TwinsUK

AF:

0.0882

AC:

327

ALSPAC

AF:

0.0895

AC:

345

ESP6500AA

AF:

0.0261

AC:

115

ESP6500EA

AF:

0.0943

AC:

811

ExAC

AF:

0.128

AC:

15533

Asia WGS

AF:

0.240

AC:

834

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Autosomal dominant pseudohypoaldosteronism type 1

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Pseudohypoaldosteronism type 2E

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.29

T;.;.;T;.

Eigen

Benign

-0.12

Eigen_PC

Benign

0.16

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

T;T;.;T;T

MetaRNN

Benign

0.0013

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;.;.;.;.

PhyloP100

2.7

PrimateAI

Uncertain

0.63

PROVEAN

Benign

-0.27

N;N;N;.;N

REVEL

Benign

0.21

Sift

Benign

0.19

T;T;T;.;T

Sift4G

Benign

0.19

T;T;T;T;T

Polyphen

0.0

B;B;B;.;B

Vest4

0.15

MPC

0.95

ClinPred

0.016

GERP RS

6.2

PromoterAI

-0.012

Neutral

(source)

Varity_R

0.081

gMVP

0.095

Mutation Taster

=98/2

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over