rs61743561

Variant names:

• chr6-43186049-G-A
• rs61743561
• NM_015089.4:c.845G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_015089.4(CUL9):​c.845G>A​(p.Gly282Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0206 in 1,614,214 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G282R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (25 hom., cov: 32)
  • Exomes 𝑓: 0.021 (430 hom.)
• Consequence: CUL9 NM_015089.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 3.92
• Publications: 12 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033248365).
• BP6: Variant 6-43186049-G-A is Benign according to our data. Variant chr6-43186049-G-A is described in ClinVar as Benign. ClinVar VariationId is 3056976.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.015 (2280/152326) while in subpopulation NFE AF = 0.024 (1631/68018). AF 95% confidence interval is 0.023. There are 25 homozygotes in GnomAd4. There are 1032 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015089.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL9	NM_015089.4	MANE Select	c.845G>A	p.Gly282Glu	missense	Exon 4 of 41	NP_055904.1	Q8IWT3-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CUL9	ENST00000252050.9	TSL:5 MANE Select	c.845G>A	p.Gly282Glu	missense	Exon 4 of 41	ENSP00000252050.4	Q8IWT3-1
	CUL9	ENST00000372647.6	TSL:1	c.845G>A	p.Gly282Glu	missense	Exon 4 of 41	ENSP00000361730.2	E9PEZ1
	CUL9	ENST00000885097.1		c.845G>A	p.Gly282Glu	missense	Exon 5 of 42	ENSP00000555156.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2281 AN: 152208 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.00441

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0124

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0240

Gnomad OTH AF: 0.0163

GnomAD2 exomes AF: 0.0149 AC: 3753 AN: 251442 AF XY: 0.0162

Gnomad AFR exome AF: 0.00369

Gnomad AMR exome AF: 0.00830

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0134

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0144

GnomAD4 exome AF: 0.0211 AC: 30919 AN: 1461888 Hom.: 430 Cov.: 32 AF XY: 0.0210 AC XY: 15255 AN XY: 727246

African (AFR) AF: 0.00338 AC: 113 AN: 33480

American (AMR) AF: 0.00910 AC: 407 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000230 AC: 6 AN: 26136

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39700

South Asian (SAS) AF: 0.0134 AC: 1157 AN: 86258

European-Finnish (FIN) AF: 0.0138 AC: 737 AN: 53416

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.0247 AC: 27446 AN: 1112010

Other (OTH) AF: 0.0172 AC: 1040 AN: 60396

GnomAD4 genome AF: 0.0150 AC: 2280 AN: 152326 Hom.: 25 Cov.: 32 AF XY: 0.0139 AC XY: 1032 AN XY: 74490

African (AFR) AF: 0.00440 AC: 183 AN: 41574

American (AMR) AF: 0.0157 AC: 240 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.0124 AC: 60 AN: 4832

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0240 AC: 1631 AN: 68018

Other (OTH) AF: 0.0161 AC: 34 AN: 2114

Alfa AF: 0.0193 Hom.: 101

Bravo AF: 0.0139

TwinsUK AF: 0.0229 AC: 85

ALSPAC AF: 0.0239 AC: 92

ESP6500AA AF: 0.00386 AC: 17

ESP6500EA AF: 0.0236 AC: 203

ExAC AF: 0.0144 AC: 1752

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	CUL9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.72
DEOGEN2	Benign	0.060	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.61	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L
PhyloP100		3.9
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.072
Sift	Benign	0.18	T
Sift4G	Benign	0.93	T
Polyphen		0.0030	B
Vest4		0.066
MPC		0.96
ClinPred		0.013	T
GERP RS		4.4
Varity_R		0.034
gMVP		0.25
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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

Other links and lift over

dbSNP: rs61743561; hg19: chr6-43153787; COSMIC: COSV99037415; COSMIC: COSV99037415;