NM_015089.4:c.31A>T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBP6

The NM_015089.4(CUL9):c.31A>T(p.Met11Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000045 in 1,556,460 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000023 ( 1 hom. )

Consequence

CUL9
NM_015089.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 2.93

Publications

0 publications found

Variant links:

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]

CUL9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.016858041).

BP6

Variant 6-43184341-A-T is Benign according to our data. Variant chr6-43184341-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2455466.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CUL9	NM_015089.4 link	c.31A>T	p.Met11Leu	missense_variant	Exon 2 of 41	ENST00000252050.9	NP_055904.1	Q8IWT3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CUL9	ENST00000252050.9 link	c.31A>T	p.Met11Leu	missense_variant	Exon 2 of 41	5	NM_015089.4	ENSP00000252050.4	Q8IWT3-1
CUL9	ENST00000372647.6 link	c.31A>T	p.Met11Leu	missense_variant	Exon 2 of 41	1		ENSP00000361730.2	E9PEZ1
CUL9	ENST00000451399.5 link	n.106A>T		non_coding_transcript_exon_variant	Exon 2 of 5	2
CUL9	ENST00000515773.5 link	n.106A>T		non_coding_transcript_exon_variant	Exon 2 of 40	2

Frequencies

GnomAD3 genomes

AF:

0.000250

AC:

AN:

151842

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000896

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000804

AC:

AN:

211478

AF XY:

0.0000708

show subpopulations

Gnomad AFR exome

AF:

0.00113

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000228

AC:

AN:

1404618

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

690862

show subpopulations

African (AFR)

AF:

0.000777

AC:

AN:

32168

American (AMR)

AF:

0.0000258

AC:

AN:

38778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23212

East Asian (EAS)

AF:

0.00

AC:

AN:

38658

South Asian (SAS)

AF:

0.00

AC:

AN:

78820

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51734

Middle Eastern (MID)

AF:

0.000181

AC:

AN:

5524

European-Non Finnish (NFE)

AF:

0.00000371

AC:

AN:

1077848

Other (OTH)

AF:

0.0000173

AC:

AN:

57876

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.000250

AC:

AN:

151842

Hom.:

Cov.:

AF XY:

0.000270

AC XY:

AN XY:

74158

show subpopulations

African (AFR)

AF:

0.000896

AC:

AN:

41274

American (AMR)

AF:

0.0000655

AC:

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10554

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2086

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.521

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.000214

Hom.:

Bravo

AF:

0.000268

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 06, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.31A>T (p.M11L) alteration is located in exon 2 (coding exon 1) of the CUL9 gene. This alteration results from a A to T substitution at nucleotide position 31, causing the methionine (M) at amino acid position 11 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

CUL9: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.087

BayesDel_addAF

Benign

-0.40

BayesDel_noAF

Benign

-0.40

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.039

T;T

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.57

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.54

T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.017

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

0.060

N;.

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Benign

0.23

N;N

REVEL

Benign

0.079

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.18

MutPred

0.28

Loss of disorder (P = 0.0926);Loss of disorder (P = 0.0926);

MVP

0.25

MPC

0.31

ClinPred

0.0035

GERP RS

1.1

Varity_R

0.050

gMVP

0.25

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

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_015089.4:c.31A>T

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