rs138169215
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Variant summary
Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2
The NM_016042.4(EXOSC3):c.328G>A(p.Val110Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,605,264 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00074 ( 3 hom. )
Consequence
EXOSC3
NM_016042.4 missense
NM_016042.4 missense
Scores
1
5
13
Clinical Significance
Conservation
PhyloP100: 7.77
Genes affected
EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]
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ACMG classification
Classification made for transcript
Verdict is Likely_benign. Variant got -4 ACMG points.
PM1
In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 19 pathogenic changes around while only 7 benign (73%) in NM_016042.4
BP4
Computational evidence support a benign effect (MetaRNN=0.08224648).
BS2
High Homozygotes in GnomAdExome4 at 3 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EXOSC3 | NM_016042.4 | c.328G>A | p.Val110Ile | missense_variant | 2/4 | ENST00000327304.10 | |
EXOSC3 | NM_001002269.2 | c.328G>A | p.Val110Ile | missense_variant | 2/3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EXOSC3 | ENST00000327304.10 | c.328G>A | p.Val110Ile | missense_variant | 2/4 | 1 | NM_016042.4 | P1 |
Frequencies
GnomAD3 genomes AF: 0.000723 AC: 110AN: 152150Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000503 AC: 122AN: 242338Hom.: 0 AF XY: 0.000534 AC XY: 70AN XY: 131138
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GnomAD4 exome AF: 0.000741 AC: 1077AN: 1452996Hom.: 3 Cov.: 30 AF XY: 0.000726 AC XY: 525AN XY: 722660
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GnomAD4 genome AF: 0.000722 AC: 110AN: 152268Hom.: 0 Cov.: 32 AF XY: 0.000833 AC XY: 62AN XY: 74448
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Pontocerebellar hypoplasia type 1B Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 10, 2022 | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 110 of the EXOSC3 protein (p.Val110Ile). This variant is present in population databases (rs138169215, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with EXOSC3-related conditions. ClinVar contains an entry for this variant (Variation ID: 210964). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Apr 27, 2017 | This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genetic Services Laboratory, University of Chicago | Aug 06, 2015 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L
MutationTaster
Benign
D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;N
REVEL
Benign
Sift
Benign
T;T
Sift4G
Benign
T;T
Polyphen
P;.
Vest4
MVP
MPC
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at