Genetic Variant EXOSC3:p.Asp132Gly (chr9-37783993-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PM5PP3_Moderate

The NM_016042.4(EXOSC3):c.395A>G(p.Asp132Gly) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D132A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.92

Publications

50 publications found

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 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOSC3 links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-37783993-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 31688.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.927

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016042.4. 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
	EXOSC3	NM_016042.4	MANE Select	c.395A>G	p.Asp132Gly	missense	Exon 2 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.395A>G	p.Asp132Gly	missense	Exon 2 of 3	NP_001002269.1	Q9NQT5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC3	ENST00000327304.10	TSL:1 MANE Select	c.395A>G	p.Asp132Gly	missense	Exon 2 of 4	ENSP00000323046.4	Q9NQT5-1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*831A>G		non_coding_transcript_exon	Exon 9 of 12	ENSP00000457548.1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*831A>G		3_prime_UTR	Exon 9 of 12	ENSP00000457548.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.069

MetaRNN

Pathogenic

0.93

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.8

PhyloP100

7.9

PrimateAI

Uncertain

0.71

PROVEAN

Pathogenic

-6.5

REVEL

Pathogenic

0.92

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0040

Polyphen

0.99

Vest4

0.99

MutPred

0.77

Loss of stability (P = 0.0884)

MVP

0.96

MPC

0.68

ClinPred

1.0

GERP RS

5.3

Varity_R

0.91

gMVP

0.82

Mutation Taster

=11/89

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over