9-37784852-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BS2_Supporting

The NM_016042.4(EXOSC3):c.193G>A(p.Val65Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000383 in 1,608,008 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0021 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00020 ( 1 hom. )

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 1.95

Publications

2 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009042144).

BP6

Variant 9-37784852-C-T is Benign according to our data. Variant chr9-37784852-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210963.

BS2

High Homozygotes in GnomAd4 at 2 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.193G>A	p.Val65Ile	missense	Exon 1 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.193G>A	p.Val65Ile	missense	Exon 1 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.193G>A	p.Val65Ile	missense	Exon 1 of 4	ENSP00000323046.4	Q9NQT5-1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*761-789G>A		intron	N/A	ENSP00000457548.1
EXOSC3	ENST00000858037.1		c.193G>A	p.Val65Ile	missense	Exon 1 of 5	ENSP00000528096.1

Frequencies

GnomAD3 genomes

AF:

0.00212

AC:

323

AN:

152244

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00728

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000589

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000470

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.000487

AC:

114

AN:

234188

AF XY:

0.000361

show subpopulations

Gnomad AFR exome

AF:

0.00641

Gnomad AMR exome

AF:

0.000211

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000457

Gnomad NFE exome

AF:

0.0000287

Gnomad OTH exome

AF:

0.000349

GnomAD4 exome

AF:

0.000202

AC:

294

AN:

1455646

Hom.:

Cov.:

AF XY:

0.000175

AC XY:

127

AN XY:

723858

show subpopulations

African (AFR)

AF:

0.00691

AC:

230

AN:

33302

American (AMR)

AF:

0.000228

AC:

AN:

43852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25946

East Asian (EAS)

AF:

0.00

AC:

AN:

39324

South Asian (SAS)

AF:

0.00

AC:

AN:

85406

European-Finnish (FIN)

AF:

0.000476

AC:

AN:

52532

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1109408

Other (OTH)

AF:

0.000416

AC:

AN:

60116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

105

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

AF:

0.00211

AC:

322

AN:

152362

Hom.:

Cov.:

AF XY:

0.00189

AC XY:

141

AN XY:

74512

show subpopulations

African (AFR)

AF:

0.00726

AC:

302

AN:

41596

American (AMR)

AF:

0.000523

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000941

Hom.:

Bravo

AF:

0.00245

ESP6500AA

AF:

0.00909

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000693

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 1B (2)

EXOSC3-related disorder (1)

Inborn genetic diseases (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0056

Eigen

Benign

-0.38

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.66

M_CAP

Benign

0.074

MetaRNN

Benign

0.0090

MetaSVM

Benign

-0.83

MutationAssessor

Benign

1.0

PhyloP100

1.9

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-0.010

REVEL

Benign

0.097

Sift

Benign

0.27

Sift4G

Benign

0.31

Polyphen

0.035

Vest4

0.21

MVP

0.48

MPC

0.13

ClinPred

0.057

GERP RS

4.3

PromoterAI

0.019

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.2

Varity_R

0.13

gMVP

0.23

Mutation Taster

=85/15

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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