chr9-37782114-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_016042.4(EXOSC3):c.498G>A(p.Gln166Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,613,092 control chromosomes in the GnomAD database, including 216,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.54 ( 22190 hom., cov: 32)

Exomes 𝑓: 0.51 ( 194562 hom. )

Consequence

EXOSC3
NM_016042.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.654

Publications

21 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 9-37782114-C-T is Benign according to our data. Variant chr9-37782114-C-T is described in ClinVar as Benign. ClinVar VariationId is 129025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.654 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4 link	c.498G>A	p.Gln166Gln	synonymous_variant	Exon 3 of 4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2 link	c.475-1234G>A		intron_variant	Intron 2 of 2		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10 link	c.498G>A	p.Gln166Gln	synonymous_variant	Exon 3 of 4	1	NM_016042.4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1 link	n.*910+1800G>A		intron_variant	Intron 9 of 11	5		ENSP00000457548.1

Frequencies

GnomAD3 genomes

AF:

0.539

AC:

81882

AN:

151878

Hom.:

22134

Cov.:

show subpopulations

Gnomad AFR

AF:

0.596

Gnomad AMI

AF:

0.523

Gnomad AMR

AF:

0.559

Gnomad ASJ

AF:

0.433

Gnomad EAS

AF:

0.534

Gnomad SAS

AF:

0.576

Gnomad FIN

AF:

0.568

Gnomad MID

AF:

0.404

Gnomad NFE

AF:

0.500

Gnomad OTH

AF:

0.534

GnomAD2 exomes

AF:

0.536

AC:

134391

AN:

250866

AF XY:

0.530

show subpopulations

Gnomad AFR exome

AF:

0.599

Gnomad AMR exome

AF:

0.621

Gnomad ASJ exome

AF:

0.431

Gnomad EAS exome

AF:

0.535

Gnomad FIN exome

AF:

0.563

Gnomad NFE exome

AF:

0.499

Gnomad OTH exome

AF:

0.520

GnomAD4 exome

AF:

0.514

AC:

751316

AN:

1461094

Hom.:

194562

Cov.:

AF XY:

0.514

AC XY:

373405

AN XY:

726846

show subpopulations

African (AFR)

AF:

0.597

AC:

19977

AN:

33460

American (AMR)

AF:

0.615

AC:

27506

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.420

AC:

10980

AN:

26122

East Asian (EAS)

AF:

0.526

AC:

20890

AN:

39692

South Asian (SAS)

AF:

0.555

AC:

47854

AN:

86220

European-Finnish (FIN)

AF:

0.568

AC:

30321

AN:

53378

Middle Eastern (MID)

AF:

0.424

AC:

2444

AN:

5766

European-Non Finnish (NFE)

AF:

0.504

AC:

560326

AN:

1111366

Other (OTH)

AF:

0.514

AC:

31018

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

17509

35019

52528

70038

87547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

16428

32856

49284

65712

82140

<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:

0.539

AC:

81993

AN:

151998

Hom.:

22190

Cov.:

AF XY:

0.539

AC XY:

40063

AN XY:

74266

show subpopulations

African (AFR)

AF:

0.596

AC:

24715

AN:

41466

American (AMR)

AF:

0.559

AC:

8541

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.433

AC:

1501

AN:

3470

East Asian (EAS)

AF:

0.534

AC:

2755

AN:

5164

South Asian (SAS)

AF:

0.577

AC:

2781

AN:

4820

European-Finnish (FIN)

AF:

0.568

AC:

5985

AN:

10536

Middle Eastern (MID)

AF:

0.408

AC:

119

AN:

292

European-Non Finnish (NFE)

AF:

0.500

AC:

33984

AN:

67960

Other (OTH)

AF:

0.538

AC:

1136

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1953

3905

5858

7810

9763

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

712

1424

2136

2848

3560

<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:

0.509

Hom.:

8578

Bravo

AF:

0.541

Asia WGS

AF:

0.558

AC:

1941

AN:

3478

EpiCase

AF:

0.481

EpiControl

AF:

0.481

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 08, 2016

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Pontocerebellar hypoplasia type 1B

Benign:4

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.65

CADD

Benign

1.0

(source)

DANN

Benign

0.61

PhyloP100

-0.65

Mutation Taster

=100/0

polymorphism (auto)

(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

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over