NM_005033.3:c.1274G>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005033.3(EXOSC9):c.1274G>C(p.Ser425Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0385 in 1,601,626 control chromosomes in the GnomAD database, including 6,769 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 (★★).

Frequency

Genomes: 𝑓 0.13 ( 3428 hom., cov: 32)

Exomes 𝑓: 0.029 ( 3341 hom. )

Consequence

EXOSC9
NM_005033.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.552

Publications

15 publications found

Variant links:

Genes affected

EXOSC9 (HGNC:9137): (exosome component 9) This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

EXOSC9 links:

CCNA2 (HGNC:1578): (cyclin A2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members function as regulators of the cell cycle. This protein binds and activates cyclin-dependent kinase 2 and thus promotes transition through G1/S and G2/M. [provided by RefSeq, Aug 2016]

CCNA2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

CCNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003394425).

BP6

Variant 4-121816810-G-C is Benign according to our data. Variant chr4-121816810-G-C is described in ClinVar as Benign. ClinVar VariationId is 1249603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.392 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005033.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC9	NM_005033.3	MANE Select	c.1274G>C	p.Ser425Thr	missense	Exon 12 of 12	NP_005024.2	Q06265-1
CCNA2	NM_001237.5	MANE Select	c.*828C>G		3_prime_UTR	Exon 8 of 8	NP_001228.2	P20248
EXOSC9	NM_001034194.2		c.1325G>C	p.Ser442Thr	missense	Exon 13 of 13	NP_001029366.1	Q06265-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.1274G>C	p.Ser425Thr	missense	Exon 12 of 12	ENSP00000243498.5	Q06265-1
EXOSC9	ENST00000379663.7	TSL:1	c.1325G>C	p.Ser442Thr	missense	Exon 13 of 13	ENSP00000368984.3	Q06265-2
EXOSC9	ENST00000512454.5	TSL:1	c.1226G>C	p.Ser409Thr	missense	Exon 11 of 11	ENSP00000425782.1	D6RIY6

Frequencies

GnomAD3 genomes

AF:

0.129

AC:

19517

AN:

151784

Hom.:

3417

Cov.:

show subpopulations

Gnomad AFR

AF:

0.397

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.0698

Gnomad ASJ

AF:

0.0503

Gnomad EAS

AF:

0.0289

Gnomad SAS

AF:

0.0102

Gnomad FIN

AF:

0.00502

Gnomad MID

AF:

0.0860

Gnomad NFE

AF:

0.0206

Gnomad OTH

AF:

0.113

GnomAD2 exomes

AF:

0.0451

AC:

10645

AN:

236040

AF XY:

0.0373

show subpopulations

Gnomad AFR exome

AF:

0.404

Gnomad AMR exome

AF:

0.0319

Gnomad ASJ exome

AF:

0.0536

Gnomad EAS exome

AF:

0.0309

Gnomad FIN exome

AF:

0.00422

Gnomad NFE exome

AF:

0.0199

Gnomad OTH exome

AF:

0.0405

GnomAD4 exome

AF:

0.0290

AC:

42045

AN:

1449724

Hom.:

3341

Cov.:

AF XY:

0.0274

AC XY:

19769

AN XY:

720714

show subpopulations

African (AFR)

AF:

0.414

AC:

13503

AN:

32592

American (AMR)

AF:

0.0363

AC:

1573

AN:

43318

Ashkenazi Jewish (ASJ)

AF:

0.0548

AC:

1416

AN:

25858

East Asian (EAS)

AF:

0.0259

AC:

1020

AN:

39408

South Asian (SAS)

AF:

0.00844

AC:

714

AN:

84602

European-Finnish (FIN)

AF:

0.00527

AC:

279

AN:

52896

Middle Eastern (MID)

AF:

0.0657

AC:

377

AN:

5738

European-Non Finnish (NFE)

AF:

0.0184

AC:

20296

AN:

1105472

Other (OTH)

AF:

0.0479

AC:

2867

AN:

59840

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

1592

3185

4777

6370

7962

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

956

1912

2868

3824

4780

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.129

AC:

19570

AN:

151902

Hom.:

3428

Cov.:

AF XY:

0.124

AC XY:

9189

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.397

AC:

16417

AN:

41366

American (AMR)

AF:

0.0695

AC:

1061

AN:

15264

Ashkenazi Jewish (ASJ)

AF:

0.0503

AC:

174

AN:

3462

East Asian (EAS)

AF:

0.0292

AC:

151

AN:

5174

South Asian (SAS)

AF:

0.00976

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00502

AC:

AN:

10562

Middle Eastern (MID)

AF:

0.0959

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0206

AC:

1400

AN:

67944

Other (OTH)

AF:

0.111

AC:

235

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

633

1266

1900

2533

3166

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

170

340

510

680

850

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0376

Hom.:

358

Bravo

AF:

0.148

TwinsUK

AF:

0.0186

AC:

ALSPAC

AF:

0.0140

AC:

ESP6500AA

AF:

0.374

AC:

1647

ESP6500EA

AF:

0.0229

AC:

197

ExAC

AF:

0.0511

AC:

6201

Asia WGS

AF:

0.0440

AC:

151

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

EXOSC9-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.0052

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.47

MetaRNN

Benign

0.0034

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

PhyloP100

0.55

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.63

REVEL

Benign

0.082

Sift

Benign

0.046

Sift4G

Benign

0.26

Polyphen

0.034

Vest4

0.12

MPC

0.059

ClinPred

0.0085

GERP RS

4.1

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.062

gMVP

0.18

Mutation Taster

=99/1

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over