NM_181503.3:c.815G>C

Variant names:

• chr13-37009283-G-C
• rs36027220
• NM_181503.3:c.815G>C

Variant summary

Our verdict is Benign. The variant received -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:4 O:1
• Conservation: PhyloP100: 9.02
• Publications: 20 publications found

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

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_181503.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC8	NM_181503.3	MANE Select	c.815G>C	p.Ser272Thr	missense	Exon 11 of 11	NP_852480.1	Q96B26
	SUPT20H	NM_001014286.3	MANE Select	c.*389C>G		downstream_gene	N/A	NP_001014308.2	Q8NEM7-1
	SUPT20H	NM_001278480.2		c.*426C>G		downstream_gene	N/A	NP_001265409.1	Q8NEM7-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC8	ENST00000389704.4	TSL:1 MANE Select	c.815G>C	p.Ser272Thr	missense	Exon 11 of 11	ENSP00000374354.3	Q96B26
	EXOSC8	ENST00000490537.6	TSL:1	n.2305G>C		non_coding_transcript_exon	Exon 10 of 10
	EXOSC8	ENST00000932950.1		c.338G>C	p.Ser113Thr	missense	Exon 6 of 6	ENSP00000603009.1

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

GnomAD2 exomes AF: 0.00385 AC: 959 AN: 248810 AF XY: 0.00397

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

African (AFR) AF: 0.000877 AC: 29 AN: 33070

American (AMR) AF: 0.00185 AC: 82 AN: 44318

Ashkenazi Jewish (ASJ) AF: 0.000770 AC: 20 AN: 25964

East Asian (EAS) AF: 0.0000253 AC: 1 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: 35 AN: 5514

European-Non Finnish (NFE) AF: 0.00683 AC: 7488 AN: 1096434

Other (OTH) AF: 0.00476 AC: 284 AN: 59702

GnomAD4 genome AF: 0.00393 AC: 599 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00336 AC XY: 250 AN XY: 74448

African (AFR) AF: 0.00106 AC: 44 AN: 41570

American (AMR) AF: 0.00157 AC: 24 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000864 AC: 3 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00132 AC: 14 AN: 10594

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00722 AC: 491 AN: 68018

Other (OTH) AF: 0.00237 AC: 5 AN: 2110

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

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	3	not provided (4)
1	2	-	Pontocerebellar hypoplasia, type 1C (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		9.0
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.49	N
REVEL	Pathogenic	0.68
Sift	Benign	0.35	T
Sift4G	Benign	0.51	T
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
Mutation Taster		=49/51	disease causing (ClinVar)

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

Other links and lift over

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