rs36027220

Positions:

chr13-37009283-G-C

Variant summary

Our verdict is Benign. Variant got -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).

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:3O:1

Conservation

PhyloP100: 9.02

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 made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

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

BS2

High Homozygotes in GnomAdExome4 at 36 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC8	NM_181503.3 link	c.815G>C	p.Ser272Thr	missense_variant	11/11	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/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC8	ENST00000389704.4 link	c.815G>C	p.Ser272Thr	missense_variant	11/11	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

GnomAD3 exomes

AF:

0.00385

AC:

959

AN:

248810

Hom.:

AF XY:

0.00397

AC XY:

534

AN XY:

134438

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 SAS exome

AF:

0.00265

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

Gnomad4 AFR exome

AF:

0.000877

Gnomad4 AMR exome

AF:

0.00185

Gnomad4 ASJ exome

AF:

0.000770

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.00236

Gnomad4 FIN exome

AF:

0.00315

Gnomad4 NFE exome

AF:

0.00683

Gnomad4 OTH exome

AF:

0.00476

GnomAD4 genome

AF:

0.00393

AC:

599

AN:

152280

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

250

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.00157

Gnomad4 ASJ

AF:

0.000864

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00332

Gnomad4 FIN

AF:

0.00132

Gnomad4 NFE

AF:

0.00722

Gnomad4 OTH

AF:

0.00237

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:3Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 1C

Pathogenic:1Uncertain:2Other:1

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 03, 2014	- -
not provided, no classification provided	phenotyping only	GenomeConnect, ClinGen	-	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. -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 24, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Pathogenic:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 06, 2020	This variant is associated with the following publications: (PMID: 27127732, 24989451, 29431110, 30581635, 29758258, 29093021, 31664448, 31980526) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 07, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EXOSC8: BS2 -

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

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;.

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

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over