NM_016042.4:c.238G>T

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4

The NM_016042.4(EXOSC3):c.238G>T(p.Val80Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00016 in 1,608,334 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00090 ( 6 hom., cov: 32)

Exomes 𝑓: 0.000083 ( 1 hom. )

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9O:1

Conservation

PhyloP100: 7.37

Variant links:

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]

EXOSC3 links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_016042.4

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, Eigen, M_CAP, PrimateAI, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

PP5

Variant 9-37784807-C-A is Pathogenic according to our data. Variant chr9-37784807-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 129024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37784807-C-A is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.19264564). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4 link	c.238G>T	p.Val80Phe	missense_variant	Exon 1 of 4	ENST00000327304.10	NP_057126.2	Q9NQT5-1
EXOSC3	NM_001002269.2 link	c.238G>T	p.Val80Phe	missense_variant	Exon 1 of 3		NP_001002269.1	Q9NQT5-2Q9NYS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10 link	c.238G>T	p.Val80Phe	missense_variant	Exon 1 of 4	1	NM_016042.4	ENSP00000323046.4		Q9NQT5-1
ENSG00000255872	ENST00000540557.1 link	n.*761-744G>T		intron_variant	Intron 8 of 11	5		ENSP00000457548.1

Frequencies

GnomAD3 genomes

AF:

0.000900

AC:

137

AN:

152252

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.00170

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000413

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000153

AC:

AN:

234882

Hom.:

AF XY:

0.000132

AC XY:

AN XY:

128502

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000238

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000436

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000142

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000831

AC:

121

AN:

1455964

Hom.:

Cov.:

AF XY:

0.0000773

AC XY:

AN XY:

724310

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000226

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000420

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000648

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.000899

AC:

137

AN:

152370

Hom.:

Cov.:

AF XY:

0.000953

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00170

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000156

Hom.:

Bravo

AF:

0.00110

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000991

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 1B

Pathogenic:6Other:1

May 04, 2022

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 21, 2014

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GeneReviews

Significance: not provided

Review Status: no classification provided

Collection Method: literature only

- -

Oct 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine, which is neutral and non-polar, with phenylalanine, which is neutral and non-polar, at codon 80 of the EXOSC3 protein (p.Val80Phe). This variant is present in population databases (rs374550999, gnomAD 0.04%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 23975261, 25809939). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 129024). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is expected to disrupt EXOSC3 protein function with a positive predictive value of 95%. For these reasons, this variant has been classified as Pathogenic. -

May 20, 2023

Neuberg Centre For Genomic Medicine, NCGM

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense c.238G>T(p.Val80Phe) variant in EXOSC3 gene has been reported previously in compound heterozygous state in individual(s) affected with intellectual disability, early onset spasticity, and cerebellar atrophy detects (Zanni et al., 2013). This variant is reported with the allele frequency of 0.02% in the gnomAD Exomes. This variant has been reported to the ClinVar database as Likely Pathogenic / Pathogenic (multiple submitters). The amino acid Val at position 80 is changed to a Phe changing protein sequence and it might alter its composition and physico-chemical properties. The amino acid change p.Val80Phe in EXOSC3 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. Multiple lines of computational evidence (Polyphen - Possibly Damaging, SIFT - Damaging, and MutationTaster - Disease causing) predict a damaging effect on protein structure and function for this variant. For these reasons, this variant has been classified as Pathogenic. -

Apr 13, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 01, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:2

Jun 01, 2020

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 27, 2024

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 30609409, 23975261, 24524299, 29656927, 29093021, 27219052, 34532947, 34426522, 25809939) -

Pontoneocerebellar hypoplasia

Pathogenic:1

Nov 10, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Val80Phe variant in EXOSC3 has been reported in 2 families with pontocereb ellar hypoplasia in the compound heterozygous state (Zanni 2013; Li 2013) and in one of the families the variant segregated in the 2 affected siblings (Zanni 20 13). This variant has been described in 0.05% (7/14042) of South Asian chromosom es by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.org; rs 374550999). Although this variant has been seen in the general population, its f requency is low enough to be consistent with a recessive carrier frequency. Com putational prediction tools and conservation analysis suggest the variant may im pact the protein function, though this information is not predictive enough to d etermine pathogenicity. In summary, although additional studies are required to fully establish its clinical significance, the p.Val80Phe variant is likely path ogenic for pontocerebellar hypoplasia in an autosomal recessive manner based upo n allelic observations in affected individuals. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Uncertain

0.15

BayesDel_noAF

Pathogenic

0.31

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

T;.

Eigen

Pathogenic

0.77

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.8

M;M

PrimateAI

Pathogenic

0.88

PROVEAN

Uncertain

-3.0

D;D

REVEL

Pathogenic

0.84

Sift

Benign

0.054

T;D

Sift4G

Uncertain

0.014

D;D

Polyphen

0.94

P;.

Vest4

0.96

MVP

0.84

MPC

0.55

ClinPred

0.77

GERP RS

5.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.8

Varity_R

0.86

gMVP

0.88

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over