rs374550999

Positions:

• chr9-37784807-C-A
• chr9-37784807-C-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1 PP3 PP5_Very_Strong BP4

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
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9 O:1
• Conservation: PhyloP100: 7.37

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]

ENSG00000255872 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
EXOSC3	NM_016042.4	c.238G>T	p.Val80Phe	missense_variant	1/4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2	c.238G>T	p.Val80Phe	missense_variant	1/3		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10	c.238G>T	p.Val80Phe	missense_variant	1/4	1	NM_016042.4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1	n.*761-744G>T		intron_variant		5		ENSP00000457548.1

Frequencies

GnomAD3 genomes AF: 0.000900 AC: 137 AN: 152252 Hom.: 6 Cov.: 32

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: 36 AN: 234882 Hom.: 0 AF XY: 0.000132 AC XY: 17 AN XY: 128502

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.: 1 Cov.: 30 AF XY: 0.0000773 AC XY: 56 AN XY: 724310

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.: 6 Cov.: 32 AF XY: 0.000953 AC XY: 71 AN XY: 74506

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.: 0

Bravo AF: 0.00110

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000991 AC: 12

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Pontocerebellar hypoplasia type 1B Pathogenic:6 Other:1

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 18, 2023	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). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt EXOSC3 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	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. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 21, 2014	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 04, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Apr 13, 2022	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2013	- -

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 27, 2024	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

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Nov 10, 2016

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	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.69	D
MetaRNN	Benign	0.19	T;T
MetaSVM	Uncertain	0.41	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Pathogenic	0.88	D
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	D
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

Other links and lift over

dbSNP: rs374550999; hg19: chr9-37784804;