9-37784953-C-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_016042.4(EXOSC3):c.92G>C(p.Gly31Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,460,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000012 ( 0 hom. )

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23O:1

Conservation

PhyloP100: 4.47

Publications

35 publications found

Variant links:

Genes affected

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

EXOSC3 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOSC3 links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 9-37784953-C-G is Pathogenic according to our data. Variant chr9-37784953-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4 link	c.92G>C	p.Gly31Ala	missense_variant	Exon 1 of 4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2 link	c.92G>C	p.Gly31Ala	missense_variant	Exon 1 of 3		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10 link	c.92G>C	p.Gly31Ala	missense_variant	Exon 1 of 4	1	NM_016042.4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1 link	n.*761-890G>C		intron_variant	Intron 8 of 11	5		ENSP00000457548.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000204

AC:

AN:

244798

AF XY:

0.0000150

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000365

Gnomad OTH exome

AF:

0.000166

GnomAD4 exome

AF:

0.0000123

AC:

AN:

1460562

Hom.:

Cov.:

AF XY:

0.0000193

AC XY:

AN XY:

726582

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44648

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26074

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52846

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000126

AC:

AN:

1111692

Other (OTH)

AF:

0.0000663

AC:

AN:

60326

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:23Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 1B

Pathogenic:17Other:1

Dec 01, 2013

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

3billion

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.002%). In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.74; 3Cnet: 0.81). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000031691 / PMID: 22544365). The variant has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 22544365). Therefore, this variant is classified as Likely pathogenic according to the recommendation of ACMG/AMP guideline. -

Mar 04, 2025

Institute of Human Genetics, University of Leipzig Medical Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Criteria applied: PM3_STR,PM1,PM2,PS3_SUP,PP3 -

Nov 28, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2025

Center of Human Genetics, Hôpital Erasme

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 25, 2022

Institute of Human Genetics, University Hospital Muenster

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG categories: PM2,PM3,PP3,PP5 -

Aug 11, 2014

Genetic Services Laboratory, University of Chicago

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department Of Human Genetics, Institute Of Clinical And Translational Research, Biomedical Research Center, Slovak Academy Of Sciences

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

The p.(Gly31Ala) variant has a low general population frequency (G = 0.000020 in gnomAD) and it has not been found in the general Slovak population (PMID: 31054297). It is frequent in Czech Roma patients (the founder effect was suggested) and 4.4 % of unrelated Czech Roma control individuals were carriers (PMID: 23883322). Slovak patients show the same or highly similar haplotype, indicating a common origin (PMID: 35852507) (there has been a close connection between the Slovak and Czech populations). Interestingly, in the study PMID: 24524299 all patients who carried this variant were of Roma/Gypsy descent, although living in different countries (Sweden and Hungary) (a common founder?) (PMID: 23284067, PMID: 23883322). The variant is in the EXOSC3 N-terminal domain that is important for intersubunit interactions: residue Gly31 has been shown tightly packed against the surface of EXOSC5, indicating its importance for EXOSC3-EXOSC5 interactions (PMID: 29093021, PMID: 27777260). Patients homozygous for this variant manifest a severe disease course including death during infancy and hypoplasia of the pons (PMID: 24524299). -

Jul 24, 2022

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM2 moderated, PM3 strong, PP1 strong, PP3 supporting -

Genomics England Pilot Project, Genomics England

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

May 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 31 of the EXOSC3 protein (p.Gly31Ala). This variant is present in population databases (rs387907196, gnomAD 0.003%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 30221345). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31691). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXOSC3 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects EXOSC3 function (PMID: 22544365, 28053271). For these reasons, this variant has been classified as Pathogenic. -

Jun 01, 2022

Solve-RD Consortium

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:provider interpretation

Variant confirmed as disease-causing by referring clinical team -

Jan 01, 2022

Provincial Medical Genetics Program of British Columbia, University of British Columbia

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 29, 2022

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 19, 2022

Revvity Omics, Revvity

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 02, 2021

Clinical Genetics Laboratory, University Hospital Schleswig-Holstein

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 02, 2024

Fulgent Genetics, Fulgent Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GeneReviews

Significance:not provided

Review Status:no classification provided

Collection Method:literature only

- -

not provided

Pathogenic:4

Oct 23, 2020

Institute of Medical Genetics and Applied Genomics, University Hospital Tübingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Nov 18, 2016

Clinical Genetics and Genomics, Karolinska University Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2022

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published yeast functional studies demonstrate a damaging effect with impaired pre-rRNA processing (Gillespie et al., 2017); Not observed at a significant frequency in large population cohorts (gnomAD); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30986545, 27777260, 27876572, 23883322, 28053271, 29096039, 22544365, 30221345, 30025162, 29656927, 34426522, 31589614, 31770597, 24524299) -

Lissencephaly;C1276035:Fetal akinesia deformation sequence 1;C1848529:Hypoplasia of the pons;C1855843:Severe intrauterine growth retardation;C1866129:Abnormal cerebellum morphology;C2673351:Paucity of anterior horn motor neurons;C4551563:Microcephaly

Pathogenic:1

Oct 09, 2019

Department of Genetics, Rouen University Hospital, Normandy Center for Genomic and Personalized Medicine

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myopathy

Pathogenic:1

Mar 01, 2024

Muscle and Diseases Team, Institut de Génétique et Biologie Moléculaire et Cellulaire

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:research

PS1+PM1+PM2+PP2+PP3+PP4+PP5 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.74

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.28

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.49

T;.

Eigen

Pathogenic

0.78

Eigen_PC

Pathogenic

0.72

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.84

T;T

M_CAP

Pathogenic

0.45

MetaRNN

Uncertain

0.71

D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

4.5

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-3.6

D;D

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

0.51

MutPred

0.42

Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);

MVP

0.89

MPC

0.62

ClinPred

0.98

GERP RS

5.3

PromoterAI

-0.10

Neutral

(source)

RBP_binding_hub_radar

0.92

RBP_regulation_power_radar

2.7

Varity_R

0.89

gMVP

0.93

Mutation Taster

=3/97

disease causing (ClinVar)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over