NM_005033.3:c.134G>C

Variant names:

• chr4-121801894-G-C
• rs545738309
• NM_005033.3:c.134G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005033.3(EXOSC9):​c.134G>C​(p.Cys45Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: EXOSC9 NM_005033.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.72
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia, type 1D

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005033.3. 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
	EXOSC9	NM_005033.3	MANE Select	c.134G>C	p.Cys45Ser	missense	Exon 2 of 12	NP_005024.2	Q06265-1
	EXOSC9	NM_001034194.2		c.134G>C	p.Cys45Ser	missense	Exon 2 of 13	NP_001029366.1	Q06265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.134G>C	p.Cys45Ser	missense	Exon 2 of 12	ENSP00000243498.5	Q06265-1
	EXOSC9	ENST00000379663.7	TSL:1	c.134G>C	p.Cys45Ser	missense	Exon 2 of 13	ENSP00000368984.3	Q06265-2
	EXOSC9	ENST00000512454.5	TSL:1	c.86G>C	p.Cys29Ser	missense	Exon 1 of 11	ENSP00000425782.1	D6RIY6

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	28
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.010	N
PhyloP100		8.7
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D
REVEL	Uncertain	0.37
Sift	Benign	0.31	T
Sift4G	Benign	0.37	T
Polyphen		0.98	D
Vest4		0.90
MutPred		0.54		Gain of glycosylation at T41 (P = 0.112)
MVP		0.30
MPC		0.088
ClinPred		0.92	D
GERP RS		5.6
PromoterAI		0.0087	Neutral
Varity_R		0.80
gMVP		0.76
Mutation Taster		=17/83	disease causing

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

Other links and lift over

dbSNP: rs545738309; hg19: chr4-122723049;