chr4-121801894-G-C

Position:

• chr4-121801894-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC9	NM_005033.3	c.134G>C	p.Cys45Ser	missense_variant	2/12	ENST00000243498.10	NP_005024.2
EXOSC9	NM_001034194.2	c.134G>C	p.Cys45Ser	missense_variant	2/13		NP_001029366.1
EXOSC9	XM_011532035.4	c.134G>C	p.Cys45Ser	missense_variant	2/11		XP_011530337.1
EXOSC9	XR_007057929.1	n.236G>C		non_coding_transcript_exon_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC9	ENST00000243498.10	c.134G>C	p.Cys45Ser	missense_variant	2/12	1	NM_005033.3	ENSP00000243498.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 25, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with EXOSC9-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with serine, which is neutral and polar, at codon 45 of the EXOSC9 protein (p.Cys45Ser). -

Computational scores

Source: dbNSFP v4.3

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;.;.;T
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.030	D
MetaRNN	Uncertain	0.57	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.010	N;N;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-4.6	D;D;D;D
REVEL	Uncertain	0.37
Sift	Benign	0.31	T;T;T;T
Sift4G	Benign	0.37	T;T;T;T
Polyphen		0.98	D;B;.;D
Vest4		0.90
MutPred		0.54		Gain of glycosylation at T41 (P = 0.112);Gain of glycosylation at T41 (P = 0.112);Gain of glycosylation at T41 (P = 0.112);.;
MVP		0.30
MPC		0.088
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.80
gMVP		0.76

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-122723049;