19-41387596-C-G

Variant names:

• chr19-41387596-C-G
• rs201468947
• NM_020158.4:c.533G>C

Variant summary

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

The NM_020158.4(EXOSC5):​c.533G>C​(p.Arg178Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000104 in 1,445,336 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R178Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: EXOSC5 NM_020158.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.38
• Publications: 1 publications found

Genes affected

EXOSC5 (HGNC:24662): (exosome component 5) Predicted to enable RNA binding activity. Involved in DNA deamination and exonucleolytic catabolism of deadenylated mRNA. Acts upstream of or within defense response to virus. Located in nucleolus; nucleoplasm; and transcriptionally active chromatin. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC5 Gene-Disease associations (from GenCC):

• cerebellar ataxia, brain abnormalities, and cardiac conduction defects

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000255730 (HGNC:):

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_020158.4. 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
	EXOSC5	NM_020158.4	MANE Select	c.533G>C	p.Arg178Pro	missense	Exon 5 of 6	NP_064543.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC5	ENST00000221233.9	TSL:1 MANE Select	c.533G>C	p.Arg178Pro	missense	Exon 5 of 6	ENSP00000221233.3	Q9NQT4
	ENSG00000255730	ENST00000540732.3	TSL:2	c.210+9077C>G		intron	N/A	ENSP00000443246.1	F5H5P2
	EXOSC5	ENST00000593771.2	TSL:3	c.599G>C	p.Arg200Pro	missense	Exon 6 of 7	ENSP00000471557.2	M0R102

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.0000104 AC: 15 AN: 1445336 Hom.: 0 Cov.: 30 AF XY: 0.00000557 AC XY: 4 AN XY: 717734

African (AFR) AF: 0.00 AC: 0 AN: 33074

American (AMR) AF: 0.00 AC: 0 AN: 41382

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25536

East Asian (EAS) AF: 0.00 AC: 0 AN: 39148

South Asian (SAS) AF: 0.0000241 AC: 2 AN: 83140

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52532

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.00000905 AC: 10 AN: 1105078

Other (OTH) AF: 0.0000502 AC: 3 AN: 59722

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.070
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		2.4
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.2	D
REVEL	Benign	0.25
Sift	Uncertain	0.014	D
Sift4G	Benign	0.21	T
Polyphen		0.98	D
Vest4		0.84
MutPred		0.47		Gain of glycosylation at R178 (P = 0.0411)
MVP		0.33
MPC		0.74
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.90
gMVP		0.83
Mutation Taster		=37/63	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201468947; hg19: chr19-41893501;