13-37009283-G-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_181503.3(EXOSC8):​c.815G>T​(p.Ser272Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S272T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOSC8 NM_181503.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.02
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC8	NM_181503.3	c.815G>T	p.Ser272Ile	missense_variant	Exon 11 of 11	ENST00000389704.4	NP_852480.1
SUPT20H	NM_001014286.3	c.*389C>A		downstream_gene_variant		ENST00000350612.11	NP_001014308.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC8	ENST00000389704.4	c.815G>T	p.Ser272Ile	missense_variant	Exon 11 of 11	1	NM_181503.3	ENSP00000374354.3
SUPT20H	ENST00000350612.11	c.*389C>A		downstream_gene_variant		1	NM_001014286.3	ENSP00000218894.10

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Dec 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.815G>T (p.S272I) alteration is located in exon 11 (coding exon 11) of the EXOSC8 gene. This alteration results from a G to T substitution at nucleotide position 815, causing the serine (S) at amino acid position 272 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	T;.
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Uncertain	0.54	D;D
MetaSVM	Benign	-0.69	T
MutationAssessor	Benign	2.0	M;.
PhyloP100		9.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-2.9	D;N
REVEL	Benign	0.22
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		1.0	D;.
Vest4		0.69
MutPred		0.36		Loss of phosphorylation at S272 (P = 0.0175);.;
MVP		0.71
MPC		0.50
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.66
gMVP		0.45
Mutation Taster		=40/60	disease causing

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;