9-37780834-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The ENST00000327304.10(EXOSC3):c.673T>C(p.Tyr225His) variant causes a missense change. The variant allele was found at a frequency of 0.0818 in 1,613,332 control chromosomes in the GnomAD database, including 6,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y225C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 417 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5633 hom. )

Consequence

EXOSC3
ENST00000327304.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.77

Publications

18 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: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0023806393).

BP6

Variant 9-37780834-A-G is Benign according to our data. Variant chr9-37780834-A-G is described in ClinVar as Benign. ClinVar VariationId is 129026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000327304.10. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC3	NM_016042.4	MANE Select	c.673T>C	p.Tyr225His	missense	Exon 4 of 4	NP_057126.2
	EXOSC3	NM_001002269.2		c.*26T>C		3_prime_UTR	Exon 3 of 3	NP_001002269.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
EXOSC3	ENST00000327304.10	TSL:1 MANE Select	c.673T>C	p.Tyr225His	missense	Exon 4 of 4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1	TSL:5	n.*910+3080T>C		intron	N/A	ENSP00000457548.1
EXOSC3	ENST00000465229.5	TSL:2	n.*26T>C		non_coding_transcript_exon	Exon 3 of 4	ENSP00000418422.1

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9643

AN:

152194

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.0950

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0938

Gnomad OTH

AF:

0.0716

GnomAD2 exomes

AF:

0.0665

AC:

16702

AN:

250994

AF XY:

0.0681

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.0419

Gnomad ASJ exome

AF:

0.0748

Gnomad EAS exome

AF:

0.000326

Gnomad FIN exome

AF:

0.0960

Gnomad NFE exome

AF:

0.0935

Gnomad OTH exome

AF:

0.0686

GnomAD4 exome

AF:

0.0837

AC:

122322

AN:

1461020

Hom.:

5633

Cov.:

AF XY:

0.0827

AC XY:

60137

AN XY:

726848

show subpopulations

African (AFR)

AF:

0.0130

AC:

434

AN:

33470

American (AMR)

AF:

0.0439

AC:

1963

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.0791

AC:

2066

AN:

26124

East Asian (EAS)

AF:

0.000328

AC:

AN:

39654

South Asian (SAS)

AF:

0.0402

AC:

3464

AN:

86240

European-Finnish (FIN)

AF:

0.0931

AC:

4954

AN:

53214

Middle Eastern (MID)

AF:

0.0797

AC:

459

AN:

5762

European-Non Finnish (NFE)

AF:

0.0938

AC:

104202

AN:

1111482

Other (OTH)

AF:

0.0790

AC:

4767

AN:

60356

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

5351

10702

16053

21404

26755

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3672

7344

11016

14688

18360

<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:

0.0632

AC:

9631

AN:

152312

Hom.:

417

Cov.:

AF XY:

0.0633

AC XY:

4711

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.0155

AC:

645

AN:

41582

American (AMR)

AF:

0.0584

AC:

893

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0801

AC:

278

AN:

3470

East Asian (EAS)

AF:

0.000771

AC:

AN:

5188

South Asian (SAS)

AF:

0.0364

AC:

176

AN:

4832

European-Finnish (FIN)

AF:

0.0950

AC:

1008

AN:

10608

Middle Eastern (MID)

AF:

0.105

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0937

AC:

6375

AN:

68020

Other (OTH)

AF:

0.0709

AC:

150

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

471

943

1414

1886

2357

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

116

232

348

464

580

<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:

0.0778

Hom.:

1732

Bravo

AF:

0.0580

TwinsUK

AF:

0.0866

AC:

321

ALSPAC

AF:

0.0885

AC:

341

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.0986

AC:

848

ExAC

AF:

0.0663

AC:

8053

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0991

EpiControl

AF:

0.0968

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Pontocerebellar hypoplasia type 1B (2)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

6.8

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Benign

0.15

Sift4G

Benign

0.35

Polyphen

0.99

Vest4

0.17

MPC

0.63

ClinPred

0.015

GERP RS

5.7

Varity_R

0.51

gMVP

0.68

Mutation Taster

=91/9

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over