6-43184835-A-G

Variant names:

• chr6-43184835-A-G
• rs9472022
• NM_015089.4:c.525A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BA1

The NM_015089.4(CUL9):​c.525A>G​(p.Leu175Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,611,420 control chromosomes in the GnomAD database, including 37,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.29 (8926 hom., cov: 32)
  • Exomes 𝑓: 0.18 (28079 hom.)
• Consequence: CUL9 NM_015089.4 synonymous
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 1.57
• Publications: 17 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 6-43184835-A-G is Benign according to our data. Variant chr6-43184835-A-G is described in ClinVar as [Benign]. Clinvar id is 3060146.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP7: Synonymous conserved (PhyloP=1.57 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.565 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4	c.525A>G	p.Leu175Leu	synonymous_variant	Exon 2 of 41	ENST00000252050.9	NP_055904.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CUL9	ENST00000252050.9	c.525A>G	p.Leu175Leu	synonymous_variant	Exon 2 of 41	5	NM_015089.4	ENSP00000252050.4
CUL9	ENST00000372647.6	c.525A>G	p.Leu175Leu	synonymous_variant	Exon 2 of 41	1		ENSP00000361730.2
CUL9	ENST00000451399.5	n.600A>G		non_coding_transcript_exon_variant	Exon 2 of 5	2
CUL9	ENST00000515773.5	n.600A>G		non_coding_transcript_exon_variant	Exon 2 of 40	2

Frequencies

GnomAD3 genomes AF: 0.290 AC: 44074 AN: 151968 Hom.: 8884 Cov.: 32

Gnomad AFR AF: 0.571

Gnomad AMI AF: 0.238

Gnomad AMR AF: 0.281

Gnomad ASJ AF: 0.134

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.236

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.153

Gnomad OTH AF: 0.240

GnomAD2 exomes AF: 0.223 AC: 55205 AN: 247442 AF XY: 0.212

Gnomad AFR exome AF: 0.578

Gnomad AMR exome AF: 0.299

Gnomad ASJ exome AF: 0.131

Gnomad EAS exome AF: 0.381

Gnomad FIN exome AF: 0.137

Gnomad NFE exome AF: 0.146

Gnomad OTH exome AF: 0.186

GnomAD4 exome AF: 0.179 AC: 261479 AN: 1459334 Hom.: 28079 Cov.: 33 AF XY: 0.179 AC XY: 129665 AN XY: 726046

African (AFR) AF: 0.576 AC: 19276 AN: 33472

American (AMR) AF: 0.299 AC: 13387 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.130 AC: 3406 AN: 26134

East Asian (EAS) AF: 0.369 AC: 14653 AN: 39686

South Asian (SAS) AF: 0.227 AC: 19601 AN: 86250

European-Finnish (FIN) AF: 0.136 AC: 6962 AN: 51048

Middle Eastern (MID) AF: 0.135 AC: 781 AN: 5768

European-Non Finnish (NFE) AF: 0.154 AC: 171498 AN: 1111888

Other (OTH) AF: 0.197 AC: 11915 AN: 60382

GnomAD4 genome AF: 0.290 AC: 44171 AN: 152086 Hom.: 8926 Cov.: 32 AF XY: 0.290 AC XY: 21540 AN XY: 74344

African (AFR) AF: 0.571 AC: 23685 AN: 41444

American (AMR) AF: 0.281 AC: 4290 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.134 AC: 464 AN: 3466

East Asian (EAS) AF: 0.383 AC: 1979 AN: 5164

South Asian (SAS) AF: 0.235 AC: 1132 AN: 4826

European-Finnish (FIN) AF: 0.137 AC: 1456 AN: 10594

Middle Eastern (MID) AF: 0.0952 AC: 28 AN: 294

European-Non Finnish (NFE) AF: 0.153 AC: 10406 AN: 67994

Other (OTH) AF: 0.243 AC: 514 AN: 2112

Alfa AF: 0.197 Hom.: 1214

Bravo AF: 0.316

Asia WGS AF: 0.304 AC: 1055 AN: 3478

EpiCase AF: 0.147

EpiControl AF: 0.142

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CUL9-related disorder Benign:1

Oct 28, 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
BayesDel_noAF	Benign	-0.61
CADD	Benign	7.9
DANN	Benign	0.86
PhyloP100		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs9472022; hg19: chr6-43152573; COSMIC: COSV52724820; COSMIC: COSV52724820;