rs199469653

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2PP5BP4

The NM_003590.5(CUL3):c.1207-3C>T variant causes a splice region, intron 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. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CUL3
NM_003590.5 splice_region, intron

Scores

Splicing: ADA: 0.2380

Clinical Significance

Pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 2.27

Publications

4 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: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 2-224503825-G-A is Pathogenic according to our data. Variant chr2-224503825-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 100519.Status of the report is no_assertion_criteria_provided, 0 stars.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.29). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL3	NM_003590.5 link	c.1207-3C>T		splice_region_variant, intron_variant	Intron 8 of 15	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.1207-3C>T		splice_region_variant, intron_variant	Intron 8 of 15	1	NM_003590.5	ENSP00000264414.4		Q13618-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

7.25e-7

AC:

AN:

1379776

Hom.:

Cov.:

AF XY:

0.00000147

AC XY:

AN XY:

681984

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30502

American (AMR)

AF:

0.0000344

AC:

AN:

29112

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22218

East Asian (EAS)

AF:

0.00

AC:

AN:

38278

South Asian (SAS)

AF:

0.00

AC:

AN:

73104

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5392

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1074058

Other (OTH)

AF:

0.00

AC:

AN:

56754

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Pseudohypoaldosteronism type 2E

Pathogenic:1

Jan 22, 2012

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Pseudohypoaldosteronism type 2A

Pathogenic:1

Richard Lifton Laboratory, Yale University School of Medicine

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.94

PhyloP100

2.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Mutation Taster

=9/91

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.24

dbscSNV1_RF

Benign

0.11

SpliceAI score (max)

0.26

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.26

Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over