chr13-37009283-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_181503.3(EXOSC8):c.815G>C(p.Ser272Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,595,800 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S272I) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0039 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0058 ( 36 hom. )

Consequence

EXOSC8
NM_181503.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:2B:4O:1

Conservation

PhyloP100: 9.02

Publications

20 publications found

Variant links:

Genes affected

EXOSC8 (HGNC:17035): (exosome component 8) This gene encodes a 3'-5' exoribonuclease that specifically interacts with mRNAs containing AU-rich elements. The encoded protein is part of the exosome complex that is important for the degradation of numerous RNA species. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Mar 2009]

EXOSC8 links:

SUPT20H (HGNC:20596): (SPT20 homolog, SAGA complex component) Predicted to enable transcription coregulator activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to act upstream of or within positive regulation of gluconeogenesis and positive regulation of transcription by RNA polymerase II. Part of SAGA-type complex. [provided by Alliance of Genome Resources, Apr 2022]

SUPT20H links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005367756).

BS2

High Homozygotes in GnomAdExome4 at 36 AR,Unknown gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC8	NM_181503.3 link	c.815G>C	p.Ser272Thr	missense_variant	Exon 11 of 11	ENST00000389704.4	NP_852480.1	Q96B26
SUPT20H	NM_001014286.3 link	c.*389C>G		downstream_gene_variant		ENST00000350612.11	NP_001014308.2	Q8NEM7-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC8	ENST00000389704.4 link	c.815G>C	p.Ser272Thr	missense_variant	Exon 11 of 11	1	NM_181503.3	ENSP00000374354.3		Q96B26
SUPT20H	ENST00000350612.11 link	c.*389C>G		downstream_gene_variant		1	NM_001014286.3	ENSP00000218894.10		Q8NEM7-1

Frequencies

GnomAD3 genomes

AF:

0.00394

AC:

599

AN:

152162

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00157

Gnomad ASJ

AF:

0.000864

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00331

Gnomad FIN

AF:

0.00132

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00722

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00385

AC:

959

AN:

248810

AF XY:

0.00397

show subpopulations

Gnomad AFR exome

AF:

0.00124

Gnomad AMR exome

AF:

0.00173

Gnomad ASJ exome

AF:

0.000801

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00297

Gnomad NFE exome

AF:

0.00625

Gnomad OTH exome

AF:

0.00412

GnomAD4 exome

AF:

0.00576

AC:

8309

AN:

1443520

Hom.:

Cov.:

AF XY:

0.00584

AC XY:

4197

AN XY:

719112

show subpopulations

African (AFR)

AF:

0.000877

AC:

AN:

33070

American (AMR)

AF:

0.00185

AC:

AN:

44318

Ashkenazi Jewish (ASJ)

AF:

0.000770

AC:

AN:

25964

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39558

South Asian (SAS)

AF:

0.00236

AC:

202

AN:

85604

European-Finnish (FIN)

AF:

0.00315

AC:

168

AN:

53356

Middle Eastern (MID)

AF:

0.00635

AC:

AN:

5514

European-Non Finnish (NFE)

AF:

0.00683

AC:

7488

AN:

1096434

Other (OTH)

AF:

0.00476

AC:

284

AN:

59702

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

367

734

1102

1469

1836

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

272

544

816

1088

1360

<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:

0.00393

AC:

599

AN:

152280

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

250

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00106

AC:

AN:

41570

American (AMR)

AF:

0.00157

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.000864

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00332

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00132

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00722

AC:

491

AN:

68018

Other (OTH)

AF:

0.00237

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

118

148

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:

0.00584

Hom.:

Bravo

AF:

0.00367

TwinsUK

AF:

0.00647

AC:

ALSPAC

AF:

0.00727

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00352

AC:

428

Asia WGS

AF:

0.00116

AC:

AN:

3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:2Benign:4Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 1C

Pathogenic:1Uncertain:2Other:1

GenomeConnect, ClinGen

Significance:not provided

Review Status:no classification provided

Collection Method:phenotyping only

GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Jul 03, 2014

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Mar 25, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:research

- -

Jan 24, 2019

Baylor Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:1Benign:3

Jan 23, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 07, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

EXOSC8: BS2 -

Mar 06, 2020

GeneDx

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 27127732, 24989451, 29431110, 30581635, 29758258, 29093021, 31664448, 31980526) -

not specified

Benign:1

May 27, 2025

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: EXOSC8 c.815G>C (p.Ser272Thr) results in a conservative amino acid change in the encoded protein sequence. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change. The variant allele was found at a frequency of 0.0039 in 248810 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency exceeds the estimated maximal expected allele frequency for a pathogenic variant in EXOSC8 causing Pontocerebellar Hypoplasia, Type 1C phenotype. c.815G>C has been observed in individual(s) affected with Pontocerebellar Hypoplasia, Type 1C, Gangliosidosis GM1, neuroinflammation, Microcephaly, without strong evidence for causality and was also reported in unaffected individuals (Boczonadi_2014, Bouhouche_2018, Cavusoglu_2024, Hou_2020, McCreary_2019, Reuter_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Pontocerebellar Hypoplasia, Type 1C. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Boczonadi_2014). The following publications have been ascertained in the context of this evaluation (PMID: 24989451, 30581635, 38622473, 31980526, 31664448, 29431110). ClinVar contains an entry for this variant (Variation ID: 157608). Based on the evidence outlined above, the variant was classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.044

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.72

T;T

M_CAP

Uncertain

0.16

MetaRNN

Benign

0.0054

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

2.0

M;.

PhyloP100

9.0

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.49

N;N

REVEL

Pathogenic

0.68

Sift

Benign

0.35

T;D

Sift4G

Benign

0.51

T;D

Polyphen

0.094

B;.

Vest4

0.57

MVP

0.54

MPC

0.15

ClinPred

0.11

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.22

gMVP

0.23

Mutation Taster

=49/51

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over