chr9-37783993-T-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3PP3_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 (★★). ClinVar reports functional evidence for this variant: "SCV003924041: Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017)." and additional evidence is available in ClinVar. 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:41

Conservation

PhyloP100: 7.92

Publications

52 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: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
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 14 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV003924041: Functionally, the variant causes dysfunctional exosome complex (Schottmann, Gudrun et al., 2017).; SCV004801434: 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).

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 VariationId is 31688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016042.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC3	NM_016042.4	MANE Select	c.395A>C	p.Asp132Ala	missense	Exon 2 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.395A>C	p.Asp132Ala	missense	Exon 2 of 3	NP_001002269.1	Q9NQT5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC3	ENST00000327304.10	TSL:1 MANE Select	c.395A>C	p.Asp132Ala	missense	Exon 2 of 4	ENSP00000323046.4	Q9NQT5-1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*831A>C		non_coding_transcript_exon	Exon 9 of 12	ENSP00000457548.1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*831A>C		3_prime_UTR	Exon 9 of 12	ENSP00000457548.1

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

GnomAD2 exomes

AF:

0.000406

AC:

102

AN:

251366

AF XY:

0.000397

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 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

African (AFR)

AF:

0.000120

AC:

AN:

33472

American (AMR)

AF:

0.000246

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26128

East Asian (EAS)

AF:

0.00

AC:

AN:

39680

South Asian (SAS)

AF:

0.000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.0000375

AC:

AN:

53404

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.000904

AC:

1005

AN:

1111954

Other (OTH)

AF:

0.000563

AC:

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

129

193

258

322

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

120

160

200

<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:

0.000480

AC:

AN:

152206

Hom.:

Cov.:

AF XY:

0.000444

AC XY:

AN XY:

74356

show subpopulations

African (AFR)

AF:

0.000193

AC:

AN:

41440

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.000414

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000911

AC:

AN:

68046

Other (OTH)

AF:

0.000478

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000156

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

ClinVar submissions

Significance:Pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 1B (26)

not provided (9)

Abnormality of the nervous system (1)

Congenital pontocerebellar hypoplasia type 1 (1)

EXOSC3-related disorder (1)

Hypotonia (1)

Inborn genetic diseases (1)

See cases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.18

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.27

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.068

MetaRNN

Pathogenic

0.91

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.6

PhyloP100

7.9

PrimateAI

Uncertain

0.69

PROVEAN

Pathogenic

-7.4

REVEL

Pathogenic

0.91

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.98

MVP

0.96

MPC

0.65

ClinPred

0.73

GERP RS

5.3

Varity_R

0.93

gMVP

0.80

Mutation Taster

=1/99

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over