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GeneBe

11-108088527-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_ModerateBP6_ModerateBP7BS2

The NM_003478.6(CUL5):c.1179G>A(p.Gly393=) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000486 in 1,583,070 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000048 ( 0 hom. )

Consequence

CUL5
NM_003478.6 splice_region, synonymous

Scores

2
Splicing: ADA: 0.002333
2

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.28
Variant links:
Genes affected
CUL5 (HGNC:2556): (cullin 5) Enables ubiquitin protein ligase binding activity. Predicted to be involved in SCF-dependent proteasomal ubiquitin-dependent protein catabolic process and protein ubiquitination. Predicted to act upstream of or within cerebral cortex radially oriented cell migration and radial glia guided migration of Purkinje cell. Located in site of DNA damage. Part of Cul5-RING ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.41).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 11-108088527-G-A is Benign according to our data. Variant chr11-108088527-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2589806.Status of the report is criteria_provided_single_submitter, 1 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=1.28 with no splicing effect.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
CUL5NM_003478.6 linkuse as main transcriptc.1179G>A p.Gly393= splice_region_variant, synonymous_variant 12/19 ENST00000393094.7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
CUL5ENST00000393094.7 linkuse as main transcriptc.1179G>A p.Gly393= splice_region_variant, synonymous_variant 12/191 NM_003478.6 P1
CUL5ENST00000531427.5 linkuse as main transcriptc.1179G>A p.Gly393= splice_region_variant, synonymous_variant, NMD_transcript_variant 12/201

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000526
AC:
8
AN:
152074
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000882
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000632
AC:
14
AN:
221434
Hom.:
0
AF XY:
0.0000832
AC XY:
10
AN XY:
120224
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000397
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000124
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000482
AC:
69
AN:
1430996
Hom.:
0
Cov.:
30
AF XY:
0.0000492
AC XY:
35
AN XY:
711516
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000578
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000508
Gnomad4 OTH exome
AF:
0.0000508
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0000526
AC:
8
AN:
152074
Hom.:
0
Cov.:
32
AF XY:
0.0000673
AC XY:
5
AN XY:
74290
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000882
Gnomad4 OTH
AF:
0.000478
Alfa
AF:
0.0000565
Hom.:
0
Bravo
AF:
0.0000302
Asia WGS
AF:
0.000289
AC:
1
AN:
3476
EpiCase
AF:
0.000165
EpiControl
AF:
0.000180

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingAmbry GeneticsJul 12, 2023This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.41
Cadd
Benign
16
Dann
Benign
0.80
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0023
dbscSNV1_RF
Benign
0.17
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs770120509; hg19: chr11-107959254; API