13-37000810-C-A

Variant names:

• chr13-37000810-C-A
• rs606231285
• NM_181503.3:c.5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 6P and 1B. PM1 PM2 PM5 BP4

The NM_181503.3(EXOSC8):​c.5C>A​(p.Ala2Glu) variant causes a missense change. The variant allele was found at a frequency of 0.0000035 in 1,429,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: EXOSC8 NM_181503.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.89
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a modified_residue N-acetylalanine (size 0) in uniprot entity EXOS8_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr13-37000810-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 157609.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.31831196).

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.5C>A	p.Ala2Glu	missense	Exon 1 of 11	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.5C>A	p.Ala2Glu	missense	Exon 1 of 11	ENSP00000374354.3	Q96B26
	EXOSC8	ENST00000490537.6	TSL:1	n.24C>A		non_coding_transcript_exon	Exon 1 of 10
	EXOSC8	ENST00000686729.1		c.5C>A	p.Ala2Glu	missense	Exon 1 of 10	ENSP00000509000.1	A0A8I5KRG4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000350 AC: 5 AN: 1429094 Hom.: 0 Cov.: 31 AF XY: 0.00000565 AC XY: 4 AN XY: 708138

African (AFR) AF: 0.00 AC: 0 AN: 32310

American (AMR) AF: 0.00 AC: 0 AN: 40282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25330

East Asian (EAS) AF: 0.00 AC: 0 AN: 37388

South Asian (SAS) AF: 0.00 AC: 0 AN: 81952

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51034

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5684

European-Non Finnish (NFE) AF: 0.00000456 AC: 5 AN: 1096096

Other (OTH) AF: 0.00 AC: 0 AN: 59018

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.66
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		4.9
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.21
Sift	Benign	0.75	T
Sift4G	Benign	0.37	T
Polyphen		0.58	P
Vest4		0.52
MutPred		0.31		Gain of disorder (P = 0.0308)
MVP		0.45
MPC		0.26
ClinPred		0.96	D
GERP RS		5.5
PromoterAI		-0.69	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.59
gMVP		0.65
Mutation Taster		=52/48	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs606231285; hg19: chr13-37574947;