rs606231285

Variant names:

• chr13-37000810-C-T
• rs606231285
• NM_181503.3:c.5C>T
• EXOSC8 p.Ala2Val

Your query was ambiguous. Multiple possible variants found:

• chr13-37000810-C-T
• chr13-37000810-C-A
• chr13-37000810-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PM2 PP5

The NM_181503.3(EXOSC8):​c.5C>T​(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000316 in 1,581,236 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. A2A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: EXOSC8 NM_181503.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.89
• Publications: 8 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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
• PP5: Variant 13-37000810-C-T is Pathogenic according to our data. 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.

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>T	p.Ala2Val	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>T	p.Ala2Val	missense	Exon 1 of 11	ENSP00000374354.3	Q96B26
	EXOSC8	ENST00000490537.6	TSL:1	n.24C>T		non_coding_transcript_exon	Exon 1 of 10
	EXOSC8	ENST00000686729.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 10	ENSP00000509000.1	A0A8I5KRG4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000280 AC: 4 AN: 1429098 Hom.: 0 Cov.: 31 AF XY: 0.00000141 AC XY: 1 AN XY: 708140

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

American (AMR) AF: 0.0000248 AC: 1 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: 0.00000274 AC: 3 AN: 1096100

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

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152138 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74298

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41444

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Benign	-0.031	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.071	T
Eigen	Benign	0.10
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.025	T
MetaRNN	Uncertain	0.59	D
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.9
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.64
Sift	Benign	0.044	D
Sift4G	Benign	0.075	T
PromoterAI		-0.60	Under-expression
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.54
gMVP		0.56
Mutation Taster		=67/33	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs606231285;

hg19: chr13-37574947;