4-121816810-G-C

Position:

chr4-121816810-G-C

Variant summary

Our verdict is Benign. Variant got -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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXOSC9	NM_005033.3 linkuse as main transcript	c.1274G>C	p.Ser425Thr	missense_variant	12/12	ENST00000243498.10	NP_005024.2
CCNA2	NM_001237.5 linkuse as main transcript	c.*828C>G		3_prime_UTR_variant	8/8	ENST00000274026.10	NP_001228.2
EXOSC9	NM_001034194.2 linkuse as main transcript	c.1325G>C	p.Ser442Thr	missense_variant	13/13		NP_001029366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC9	ENST00000243498.10 linkuse as main transcript	c.1274G>C	p.Ser425Thr	missense_variant	12/12	1	NM_005033.3	ENSP00000243498	P1	Q06265-1
CCNA2	ENST00000274026.10 linkuse as main transcript	c.*828C>G		3_prime_UTR_variant	8/8	1	NM_001237.5	ENSP00000274026	P1

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

GnomAD3 exomes

AF:

0.0451

AC:

10645

AN:

236040

Hom.:

1323

AF XY:

0.0373

AC XY:

4760

AN XY:

127648

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 SAS exome

AF:

0.00748

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

Gnomad4 AFR exome

AF:

0.414

Gnomad4 AMR exome

AF:

0.0363

Gnomad4 ASJ exome

AF:

0.0548

Gnomad4 EAS exome

AF:

0.0259

Gnomad4 SAS exome

AF:

0.00844

Gnomad4 FIN exome

AF:

0.00527

Gnomad4 NFE exome

AF:

0.0184

Gnomad4 OTH exome

AF:

0.0479

GnomAD4 genome

AF:

0.129

AC:

19570

AN:

151902

Hom.:

3428

Cov.:

AF XY:

0.124

AC XY:

9189

AN XY:

74266

show subpopulations

Gnomad4 AFR

AF:

0.397

Gnomad4 AMR

AF:

0.0695

Gnomad4 ASJ

AF:

0.0503

Gnomad4 EAS

AF:

0.0292

Gnomad4 SAS

AF:

0.00976

Gnomad4 FIN

AF:

0.00502

Gnomad4 NFE

AF:

0.0206

Gnomad4 OTH

AF:

0.111

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

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

EXOSC9-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 06, 2019

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

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.60

CADD

Benign

DANN

Benign

0.91

DEOGEN2

Benign

0.0052

T;.;T

Eigen

Benign

-0.42

Eigen_PC

Benign

-0.25

FATHMM_MKL

Uncertain

0.78

LIST_S2

Benign

0.47

T;T;T

MetaRNN

Benign

0.0034

T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.2

L;.;.

MutationTaster

Benign

4.4e-14

P;P;P;P

PrimateAI

Benign

0.31

PROVEAN

Benign

-0.63

N;N;N

REVEL

Benign

0.082

Sift

Benign

0.046

D;D;D

Sift4G

Benign

0.26

T;T;T

Polyphen

0.034

B;B;B

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over