chr13-37000812-G-T

Position:

• chr13-37000812-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_181503.3(EXOSC8):​c.7G>T​(p.Ala3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000699 in 1,430,146 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. A3A) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: EXOSC8 NM_181503.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12

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]

ALG5 (HGNC:20266): (ALG5 dolichyl-phosphate beta-glucosyltransferase) This gene encodes a member of the glycosyltransferase 2 family. The encoded protein participates in glucosylation of the oligomannose core in N-linked glycosylation of proteins. The addition of glucose residues to the oligomannose core is necessary to ensure substrate recognition, and therefore, effectual transfer of the oligomannose core to the nascent glycoproteins. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17257762).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC8	NM_181503.3	c.7G>T	p.Ala3Ser	missense_variant	1/11	ENST00000389704.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC8	ENST00000389704.4	c.7G>T	p.Ala3Ser	missense_variant	1/11	1	NM_181503.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.99e-7 AC: 1 AN: 1430146 Hom.: 0 Cov.: 30 AF XY: 0.00000141 AC XY: 1 AN XY: 708698

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000122

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 19, 2022

The c.7G>T (p.A3S) alteration is located in exon 1 (coding exon 1) of the EXOSC8 gene. This alteration results from a G to T substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 to be replaced by a serine (S). 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	0.14
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Benign	0.028
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.025	T
MetaRNN	Benign	0.17	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.3	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.16
Sift	Benign	0.43	T
Sift4G	Benign	0.58	T
Polyphen		0.017	B
Vest4		0.30
MutPred		0.21		Gain of catalytic residue at A2 (P = 0.0065);
MVP		0.34
MPC		0.15
ClinPred		0.90	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.30
gMVP		0.39

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: rs967834528; hg19: chr13-37574949;