chr9-37783993-T-G

Position:

chr9-37783993-T-G

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PM2PP3_ModeratePP5_Very_Strong

The NM_016042.4(EXOSC3):c.395A>C(p.Asp132Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000706 in 1,613,954 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. D132D) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00048 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 0 hom. )

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:38

Conservation

PhyloP100: 7.92

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 19 pathogenic changes around while only 7 benign (73%) in NM_016042.4

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.909

PP5

Variant 9-37783993-T-G is Pathogenic according to our data. Variant chr9-37783993-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 31688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37783993-T-G is described in Lovd as [Likely_pathogenic]. Variant chr9-37783993-T-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC3	NM_016042.4 linkuse as main transcript	c.395A>C	p.Asp132Ala	missense_variant	2/4	ENST00000327304.10
EXOSC3	NM_001002269.2 linkuse as main transcript	c.395A>C	p.Asp132Ala	missense_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC3	ENST00000327304.10 linkuse as main transcript	c.395A>C	p.Asp132Ala	missense_variant	2/4	1	NM_016042.4	P1	Q9NQT5-1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000911

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000406

AC:

102

AN:

251366

Hom.:

AF XY:

0.000397

AC XY:

AN XY:

135850

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.000231

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000748

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000729

AC:

1066

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000747

AC XY:

543

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.000120

Gnomad4 AMR exome

AF:

0.000246

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.0000375

Gnomad4 NFE exome

AF:

0.000904

Gnomad4 OTH exome

AF:

0.000563

GnomAD4 genome

AF:

0.000480

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000911

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000469

Hom.:

Bravo

AF:

0.000416

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00128

AC:

ExAC

AF:

0.000321

AC:

EpiCase

AF:

0.000873

EpiControl

AF:

0.000830

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:38

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 1B

Pathogenic:25

Pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 08, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Dec 14, 2023	Criteria applied: PM3_VSTR,PS3_SUP,PM2_SUP,PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2013	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Dec 03, 2017	- -
Pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, Cologne University	Sep 30, 2020	- -
Pathogenic, no assertion criteria provided	literature only	GeneReviews	Apr 22, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Greenwood Genetic Center Diagnostic Laboratories, Greenwood Genetic Center	Oct 25, 2021	PM3_VS, PP1, PP3, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.395A>C;p.(Asp132Ala) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (ClinVar ID: 31688; PMID: 23975261; 28687512; 30986545; 23564332; 23564332; 29656927; 24524299; 27146152; 24970098; 23883322; 22544365) -. PS4.The variant is present at low allele frequencies population databases (rs141138948– gnomAD 0.004796%; ABraOM 0.000854 frequency - http://abraom.ib.usp.br/) - PM2_supporting. The p.(Asp132Ala) was detected in trans with a pathogenic variant (PMID: 23975261; 28687512; 23564332; 23564332; 24524299; 24524299; 27146152) -PM3_very strong The variant co-segregated with disease in multiple affected family members (PMID: 23975261; 30986545; 23564332; 27146152) - PP1_strong. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	This sequence change replaces aspartic acid, which is acidic and polar, with alanine, which is neutral and non-polar, at codon 132 of the EXOSC3 protein (p.Asp132Ala). This variant is present in population databases (rs141138948, gnomAD 0.07%). This missense change has been observed in individuals with pontocerebellar hypoplasia (PMID: 22544365, 23975261, 24524299, 25533962). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 31688). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on EXOSC3 protein function. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on EXOSC3 function (PMID: 22544365, 27777260, 28687512). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 26, 2022	- -
Pathogenic, criteria provided, single submitter	research	Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris	Jan 04, 2021	- -
Pathogenic, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	Dec 03, 2018	The homozygous p.Asp132Ala variant in EXOSC3 was identified by our study in one individual with pontocerebellar hypoplasia. The p.Asp132Ala variant in EXOSC3 has been reported in 28 individuals with pontocerebellar hypoplasia, segregated with disease in 28 individuals with pontocerebellar hypoplasia with a variety of ethnic backgrounds (including Cuban, Canadian, European, Turkish, American, and Australian) and segregated with disease in 4 affected relatives from 2 families (PMID: 29656927, 22544365, 23975261, 24524299), and has been identified in 0.07279% (94/129130) of European (non-Finnish) chromosome by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs141138948). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservational analyses suggest that this variant may impact the protein, though this information is not predictive enough to determine pathogenicity. The presence of this variant in combination with 8 variants (including 3 loss of function variants) and in individuals with pontocerebellar hypoplasia increases the likelihood that the p.Asp132Ala variant is pathogenic (PMID: 23975261, 22544365, 24524299; Variation ID: 129024, 31690, 488793, 31689). In summary, this variant meets criteria to be classified as pathogenic for pontocerebellar hypoplasia in an autosomal recessive manner based on the predicted impact of the variant and multiple occurrences with reported pathogenic EXOSC3 variants in individuals with the disease. ACMG/AMP Criteria applied: PM2, PP3, PM3_VeryStrong, PP1_Moderate (Richards 2015). -
Pathogenic, no assertion criteria provided	research	Division of Human Genetics, Children's Hospital of Philadelphia	Apr 05, 2016	- -
Pathogenic, criteria provided, single submitter	clinical testing	New York Genome Center	Jun 30, 2020	The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 [PMID: 22544365; PMID: 25149867; PMID: 23975261; PMID: 24524299; PMID: 29656927]. This variant has a frequency of 0.05% (69 heterozygous out of 143304 alleles) in gnomAD database which is low enough to be consistent with a recessive carrier frequency. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Based on the available evidence, the variant c.395A>C, p.Asp132Ala in the EXOSC3 gene is classified as pathogenic. -
Likely pathogenic, no assertion criteria provided	provider interpretation	Solve-RD Consortium	Jun 01, 2022	Variant confirmed as disease-causing by referring clinical team -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Dec 12, 2018	The EXOSC3 c.395A>C p.(Asp132Ala) missense variant has been identified in individuals with a phenotype consistent with pontocerebellar hypoplasia (Wan et al. 2012; Biancheri et al. 2013; Rudnik-Schöneborn et al. 2013; Zanni et al. 2013; Eggens et al. 2014; Schottman et al. 2017). At least one study indicated that a milder phenotype was observed when the variant was present in a homozygous state, but was more severe in individuals carrying the variant in a compound heterozygous state (Rudnik-Schöneborn et al. 2013). The highest frequency of this allele in the Genome Aggregation Database is 0.000904 in the European (non-Finnish) population (version 2.1.1). Morpholino knockdown of exosc3 in zebrafish embryos recapitulated the human phenotype; rescue of the abnormal phenotype was less effective with variant protein than wildtype protein (Wan et al. 2012). Functional studies in patient fibroblasts showed that the variant protein was largely retained in the cytosol and Golgi system compared with the speckled distribution in the nucleus of control cells (Schottman et al. 2017). Additionally, structural models in yeast Rrp40 demonstrate that the p.Asp132Ala variant impairs formation of a loop in the S1 domain, which is essential for interfacing with EXOSC5 and EXOSC9 (Fasken et al. 2017). Based on the collective evidence, the c.395A>C p.(Asp132Ala)variant is classified as pathogenic for pontocerebellar hypoplasia. -
Pathogenic, criteria provided, single submitter	not provided	Institute of Human Genetics, University Hospital of Duesseldorf	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	May 27, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 25, 2021	ACMG classification criteria: PS4 moderate, PM2 moderate, PM3 very strong, PP1 strong, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Sep 01, 2017	This mutation has been previously reported as disease-causing and was found once in our laboratory homozygous in a 7-year-old male with severe intellectual disability, hypotonia, progressive dystonia, dysmorphism, microcephaly, progressive contractures, failure to thrive, and a similarly affected sibling -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Mar 10, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics, University of Leipzig	Mar 07, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Mar 31, 2022	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0102 - Loss of function is a known mechanism of disease in this gene and is associated with pontocerebellar hypoplasia, type 1B (MIM#614678). (I) 0106 - This gene is associated with autosomal recessive disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from aspartic acid to alanine. (I) 0252 - This variant is homozygous. (I) 0304 - Variant is present in gnomAD v2 <0.01 for a recessive condition (115 heterozygotes, 0 homozygotes). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (9 heterozygotes, 0 homozygotes). (I) 0501 - Missense variant consistently predicted to be damaging by multiple in silico tools or highly conserved with a major amino acid change. (SP) 0600 - Variant is located in the annotated RNA binding S1 domain (PMID: 22544365). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported multiple times as pathogenic and likely pathogenic, and has been reported in many homozygous and compound heterozygous patients with pontocerebellar hypoplasia (ClinVar, PMID: 22544365). (SP) 1209 - This variant has been shown to be both maternally and paternally inherited (biallelic) (by trio analysis). (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Lifecell International Pvt. Ltd	-	A Homozygote Missense variant c.395A>C in Exon 2 of the EXOSC3 gene that results in the amino acid substitution p.Asp132Ala was identified. The observed variant has a minor allele frequency of 0.00041/0.00041% in gnomAD exomes and genomes, respectively. The severity of the impact of this variant on the protein is medium, based on the effect of the protein and REVEL score. Rare Exome Variant Ensemble Learner (REVEL) is an ensembl method for predicting the pathogenicity of missense variants based on a combination of scores from 13 individual tools: MutPred, FATHMM v2.3, VEST 3.0, PolyPhen-2, SIFT, PROVEAN, MutationAssessor, MutationTaster, LRT, GERP++, SiPhy, phyloP, and phastCons. The REVEL score for an individual missense variant can range from 0 to 1, with higher scores reflecting greater likelihood that the variant is disease-causing. The variant has been reported to ClinVar as Pathogenic with a status of (2 stars) criteria provided, multiple submitters, no conflicts (Variation ID 31688 as of 2022-12-24). The c.395A>C, p.Asp132Ala missense variant identified in the EXOSC3 gene has been reported previously in multiple unrelated individuals with pontocerebellar hypoplasia type 1 (Wan, Jijun et al., 2012). Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017). Based on the above evidence this variant has been classified as Pathogenic according to the ACMG guidelines. -

not provided

Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 08, 2017	- -
Pathogenic, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 26, 2021	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 23284067, 8147499, 22544365, 24524299, 23564332, 27777260, 25533962, 28687512, 11110791, 25326635, 30950035, 31692161, 30986545, 23975261, 31130284, 31980526, 33462000, 32645003, 31589614, 33163565, 33144682) -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jun 18, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	EXOSC3: PM3:Very Strong, PP1:Strong, PM2 -
Pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2021	- -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

EXOSC3-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 20, 2024

The EXOSC3 c.395A>C variant is predicted to result in the amino acid substitution p.Asp132Ala. This variant has been reported as causative for pontocerebellar hypoplasia in both the homozygous and compound heterozygous states (Wan et al. 2012. PubMed ID: 22544365; Eggens et al. 2014. PubMed ID: 24524299; Fasken et al. 2017. PubMed ID: 27777260). This variant is reported in 0.073% of alleles in individuals of European (Non-Finnish) descent in gnomAD. This variant is interpreted as pathogenic. -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 03, 2021

The c.395A>C (p.D132A) alteration is located in exon 2 (coding exon 2) of the EXOSC3 gene. This alteration results from an A to C substitution at nucleotide position 395, causing the aspartic acid (D) at amino acid position 132 to be replaced by an alanine (A). Based on data from the Genome Aggregation Database (gnomAD), the EXOSC3 c.395A>C alteration was observed in 0.04% (115/282766) of total alleles studied, with a frequency of 0.07% (94/129130) in the European (non-Finnish) subpopulation. The c.395A>C (p.D132A) alteration is the most common cause of EXOSC3-related pontocerebellar hypoplasia. This mutation has been reported in multiple affected individuals in the homozygous or compound heterozygous state (Wan, 2012; Biancheri, 2013; Eggens, 2014). The p.D132A alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

See cases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Personalized Medicine, Children's Hospital Los Angeles

Dec 21, 2022

- -

Hypotonia

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Sep 04, 2016

- -

Abnormality of the nervous system

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Kariminejad - Najmabadi Pathology & Genetics Center

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

T;.

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.91

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.6

M;M

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

D;D

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.99

D;.

Vest4

0.98

MVP

0.96

MPC

0.65

ClinPred

0.73

GERP RS

5.3

Varity_R

0.93

gMVP

0.80

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