Genetic Variant NM_003478.6:c.225A>G (chr11-108046360-A-G) – ACMG Classification: Benign (-18 pts)

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_ModerateBP6_Very_StrongBA1

The NM_003478.6(CUL5):c.225A>G(p.Gln75Gln) variant causes a synonymous change. The variant allele was found at a frequency of 0.649 in 1,597,410 control chromosomes in the GnomAD database, including 341,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.60 ( 28662 hom., cov: 33)

Exomes 𝑓: 0.65 ( 312729 hom. )

Consequence

CUL5
NM_003478.6 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 4.34

Publications

23 publications found

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]

CUL5 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -18 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.069).

BP6

Variant 11-108046360-A-G is Benign according to our data. Variant chr11-108046360-A-G is described in ClinVar as [Benign]. Clinvar id is 1272688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL5	NM_003478.6 link	c.225A>G	p.Gln75Gln	synonymous_variant	Exon 3 of 19	ENST00000393094.7	NP_003469.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL5	ENST00000393094.7 link	c.225A>G	p.Gln75Gln	synonymous_variant	Exon 3 of 19	1	NM_003478.6	ENSP00000376808.2		Q93034

Frequencies

GnomAD3 genomes

AF:

0.598

AC:

90875

AN:

152006

Hom.:

28648

Cov.:

show subpopulations

Gnomad AFR

AF:

0.400

Gnomad AMI

AF:

0.618

Gnomad AMR

AF:

0.703

Gnomad ASJ

AF:

0.667

Gnomad EAS

AF:

0.899

Gnomad SAS

AF:

0.724

Gnomad FIN

AF:

0.645

Gnomad MID

AF:

0.693

Gnomad NFE

AF:

0.650

Gnomad OTH

AF:

0.638

GnomAD2 exomes

AF:

0.676

AC:

168608

AN:

249538

AF XY:

0.678

show subpopulations

Gnomad AFR exome

AF:

0.392

Gnomad AMR exome

AF:

0.752

Gnomad ASJ exome

AF:

0.658

Gnomad EAS exome

AF:

0.898

Gnomad FIN exome

AF:

0.638

Gnomad NFE exome

AF:

0.656

Gnomad OTH exome

AF:

0.675

GnomAD4 exome

AF:

0.654

AC:

945040

AN:

1445286

Hom.:

312729

Cov.:

AF XY:

0.656

AC XY:

472542

AN XY:

719950

show subpopulations

African (AFR)

AF:

0.386

AC:

12799

AN:

33184

American (AMR)

AF:

0.742

AC:

32769

AN:

44154

Ashkenazi Jewish (ASJ)

AF:

0.666

AC:

17296

AN:

25978

East Asian (EAS)

AF:

0.900

AC:

35522

AN:

39476

South Asian (SAS)

AF:

0.714

AC:

61054

AN:

85552

European-Finnish (FIN)

AF:

0.637

AC:

33950

AN:

53328

Middle Eastern (MID)

AF:

0.647

AC:

3698

AN:

5718

European-Non Finnish (NFE)

AF:

0.646

AC:

708918

AN:

1098106

Other (OTH)

AF:

0.653

AC:

39034

AN:

59790

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

13337

26674

40010

53347

66684

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.598

AC:

90930

AN:

152124

Hom.:

28662

Cov.:

AF XY:

0.605

AC XY:

45002

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.400

AC:

16582

AN:

41486

American (AMR)

AF:

0.703

AC:

10750

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.667

AC:

2313

AN:

3470

East Asian (EAS)

AF:

0.899

AC:

4667

AN:

5192

South Asian (SAS)

AF:

0.724

AC:

3487

AN:

4818

European-Finnish (FIN)

AF:

0.645

AC:

6819

AN:

10572

Middle Eastern (MID)

AF:

0.690

AC:

203

AN:

294

European-Non Finnish (NFE)

AF:

0.650

AC:

44189

AN:

67986

Other (OTH)

AF:

0.643

AC:

1356

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1739

3479

5218

6958

8697

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.639

Hom.:

138890

Bravo

AF:

0.592

Asia WGS

AF:

0.781

AC:

2712

AN:

3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 29, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

4.3

PromoterAI

0.011

Neutral

(source)

Mutation Taster

=96/4

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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NM_003478.6:c.225A>G

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