NM_181503.3:c.17+1G>T

Variant names:

• chr13-37000823-G-T
• rs1412754843
• NM_181503.3:c.17+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_181503.3(EXOSC8):​c.17+1G>T variant causes a splice donor, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: EXOSC8 NM_181503.3 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.12
• 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]

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]

ALG5 Gene-Disease associations (from GenCC):

• polycystic kidney disease 7

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• autosomal dominant polycystic kidney disease

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.17+1G>T		splice_donor intron	N/A	NP_852480.1	Q96B26

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC8	ENST00000389704.4	TSL:1 MANE Select	c.17+1G>T		splice_donor intron	N/A	ENSP00000374354.3	Q96B26
	EXOSC8	ENST00000490537.6	TSL:1	n.36+1G>T		splice_donor intron	N/A
	EXOSC8	ENST00000685624.1		c.-2108G>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	ENSP00000510384.1	A0A8I5KNS0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1426678 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 706792

African (AFR) AF: 0.00 AC: 0 AN: 32110

American (AMR) AF: 0.00 AC: 0 AN: 40134

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25170

East Asian (EAS) AF: 0.00 AC: 0 AN: 37068

South Asian (SAS) AF: 0.00 AC: 0 AN: 81868

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51054

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1094766

Other (OTH) AF: 0.00 AC: 0 AN: 58838

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Pontocerebellar hypoplasia, type 1C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Uncertain	0.93	D
PhyloP100		6.1
GERP RS		5.7
PromoterAI		-0.68	Under-expression
Mutation Taster		=17/83	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.95		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.95		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1412754843; hg19: chr13-37574960;