rs36027220

chr13-37009283-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:2 B:3 O:1
• Conservation: PhyloP100: 9.02

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]

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]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005367756).
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC8	NM_181503.3	c.815G>C	p.Ser272Thr	missense_variant	11/11	ENST00000389704.4
SUPT20H	NM_001014286.3			downstream_gene_variant		ENST00000350612.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC8	ENST00000389704.4	c.815G>C	p.Ser272Thr	missense_variant	11/11	1	NM_181503.3	P1
SUPT20H	ENST00000350612.11			downstream_gene_variant		1	NM_001014286.3	A1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152162 Hom.: 1 Cov.: 32

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.: 2 AF XY: 0.00397 AC XY: 534 AN XY: 134438

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.: 36 Cov.: 27 AF XY: 0.00584 AC XY: 4197 AN XY: 719112

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.: 1 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74448

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.: 4

Bravo AF: 0.00367

TwinsUK AF: 0.00647 AC: 24

ALSPAC AF: 0.00727 AC: 28

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00535 AC: 46

ExAC AF: 0.00352 AC: 428

Asia WGS AF: 0.00116 AC: 4 AN: 3474

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:2 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Pontocerebellar hypoplasia, type 1C Pathogenic:1 Uncertain:2 Other:1

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]. -
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	- -

not provided Pathogenic:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EXOSC8: BS2 -
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	GeneDx	Mar 06, 2020	This variant is associated with the following publications: (PMID: 27127732, 24989451, 29431110, 30581635, 29758258, 29093021, 31664448, 31980526) -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.28
Cadd	Benign	21
Dann	Benign	0.89
DEOGEN2	Benign	0.044	T;.
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.72	T;T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0054	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.54	T
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	T
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

Other links and lift over

dbSNP: rs36027220; hg19: chr13-37583420; COSMIC: COSV99524146; COSMIC: COSV99524146;