rs139632595

Positions:

chr4-121801465-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2PP5_Very_Strong

The NM_005033.3(EXOSC9):c.41T>C(p.Leu14Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000483 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000028 ( 0 hom. )

Consequence

EXOSC9
NM_005033.3 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:14

Conservation

PhyloP100: 6.93

Variant links:

Genes affected

EXOSC9 (HGNC:9137): (exosome component 9) This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

EXOSC9 links:

EXOSC9 (HGNC:):

EXOSC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-121801465-T-C is Pathogenic according to our data. Variant chr4-121801465-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 549845.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-121801465-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC9	NM_005033.3 linkuse as main transcript	c.41T>C	p.Leu14Pro	missense_variant	1/12	ENST00000243498.10	NP_005024.2	Q06265-1
EXOSC9	NM_001034194.2 linkuse as main transcript	c.41T>C	p.Leu14Pro	missense_variant	1/13		NP_001029366.1	Q06265-2
EXOSC9	XM_011532035.4 linkuse as main transcript	c.41T>C	p.Leu14Pro	missense_variant	1/11		XP_011530337.1	B4DXG8
EXOSC9	XR_007057929.1 linkuse as main transcript	n.143T>C		non_coding_transcript_exon_variant	1/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC9	ENST00000243498.10 linkuse as main transcript	c.41T>C	p.Leu14Pro	missense_variant	1/12	1	NM_005033.3	ENSP00000243498.5		Q06265-1

Frequencies

GnomAD3 genomes

AF:

0.000243

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000597

AC:

AN:

251418

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135900

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000280

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00108

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000243

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000269

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.000865

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000529

Hom.:

Bravo

AF:

0.000238

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 1D

Pathogenic:10

Pathogenic, no assertion criteria provided	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Oct 11, 2020	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Mar 22, 2022	Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000549845, PMID:29727687). The variant has been observed in multiple (>3) similarly affected unrelated individuals (PMID: 29727687, 30125339). It has been reported to be in trans with a pathogenic variant as either compound heterozygous or homozygous in at least one similarly affected unrelated individual (PMID: 29727687) In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.606>=0.6). It is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: 0.0000832). Therefore, this variant is classified as pathogenic according to the recommendation of ACMG/AMP guideline. -
Pathogenic, no assertion criteria provided	literature only	OMIM	May 25, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 13, 2020	- -
Pathogenic, no assertion criteria provided	clinical testing	Centre for Arab Genomic Studies, Sheikh Hamdan Award for Medical Sciences	Jun 15, 2018	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Dec 29, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital	Mar 19, 2020	The p.Leu14Pro variant in EXOSC9 has been previously reported in the homozygous state in 5 unrelated individuals affected with Cerebellar Atrophy With Spinal Motor Neuronopathy (PMID: 29727687, 30125339, 29878067) and in another affected individual who was compound heterozygous with another pathogenic loss of function variant in EXOSC9 (PMID: 29727687). Functional analysis of patient fibroblasts and skeletal muscle showed reduced EXOSC9 protein expression along with reduction of the whole multi-subunit exosome complex (PMID: 29727687). Furthermore, RNA sequencing of patient cells detected significant >2-fold changes in genes involved in neuronal development and cerebellar and motor neuron degeneration. Studies in zebrafish recapitulate aspects of the human phenotype (PMID: 29727687). The p.Leu14Pro variant is observed in 21/24970(0.084%; 0 homozygotes) African alleles in the Genome Aggregation Database (gnomAD). In summary this variant meets our criteria to be classified as pathogenic. This variant is found in homozygous state in the individual and heterozygous state in both the parents, who are reported to be consanguineous. The clinical features of the patient highly correlate with the reported features of other patients carrying this variant. Recessive variants in EXOSC9 are associated with Pontocerebellar hypoplasia, type 1d, a severe, early onset progressive, SMS-like motor neuronopathy and cerebellar atrophy. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 14, 2024	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 22, 2024	This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 14 of the EXOSC9 protein (p.Leu14Pro). This variant is present in population databases (rs139632595, gnomAD 0.08%). This missense change has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 29727687, 30690203). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 549845). 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 EXOSC9 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	GeneDx	Nov 22, 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: 34645488, 29758258, 30690203, 31130284, 33040083, 32504085, 37644014, 36703223, 33258288, 34782754, 35893425, 29878067, 29727687, 30125339) -

Cerebral atrophy

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Oct 01, 2020

The homozygous p.Leu14Pro variant in EXOSC9 was identified by our study in an individual with pontocerebellar hypoplasia (PMID: 29727687). The p.Leu14Pro variant has also been reported in 5 additional individuals with pontocerebellar hypoplasia (PMID: 29727687, 30690203, 30125339), and has been identified in 0.084% (21/24970) of African chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs139632595). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. This variant has been reported pathogenic by OMIM, Al Jalila Children's Genomics Center,Al Jalila Childrens Speciality Hospital, Sheikh Hamdan Award for Medical Sciences, and Mendelics in ClinVar (Variation ID: 549845). Of the 6 affected individuals, 5 of those were homozygotes and 1 was a compound heterozygote that carried a reported likely pathogenic variants in trans, which increases the likelihood that the p.Leu14Pro variant is pathogenic (PMID: 29727687, 30690203, 30125339). The phenotype of individuals homozygous for this variant is highly specific for pontocerebellar hypoplasia based on the unique phenotype consistent with disease (PMID: 29727687). In vitro functional studies provide some evidence that the p.Leu14Pro variant may impact protein function (PMID: 29727687). However, these types of assays may not accurately represent biological function. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, although additional studies are required to fully establish its clinical significance, this variant is likely pathogenic for autosomal recessive pontocerebellar hypoplasia. ACMG/AMP Criteria applied: PM3_strong, PS3_moderate, PP4 (Richards 2015). -

Pontoneocerebellar hypoplasia

Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PM3_Strong, PS3, PP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.023

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.41

T;.;.

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

D;D;D

M_CAP

Uncertain

0.20

MetaRNN

Uncertain

0.63

D;D;D

MetaSVM

Benign

-0.34

MutationAssessor

Pathogenic

2.9

M;M;.

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Uncertain

0.61

Sift

Uncertain

0.0010

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;.

Vest4

0.87

MVP

0.72

MPC

0.49

ClinPred

0.88

GERP RS

5.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.95

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