Genetic Variant EXOSC5:p.Arg178Gln (chr19-41387596-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_020158.4(EXOSC5):c.533G>A(p.Arg178Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000128 in 1,597,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000099 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00013 ( 0 hom. )

Consequence

EXOSC5
NM_020158.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 2.38

Variant links:

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 links:

ENSG00000255730 (HGNC:):

ENSG00000255730 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.033602387).

BP6

Variant 19-41387596-C-T is Benign according to our data. Variant chr19-41387596-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1879440.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC5	NM_020158.4 link	c.533G>A	p.Arg178Gln	missense_variant	Exon 5 of 6	ENST00000221233.9	NP_064543.3	Q9NQT4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC5	ENST00000221233.9 link	c.533G>A	p.Arg178Gln	missense_variant	Exon 5 of 6	1	NM_020158.4	ENSP00000221233.3		Q9NQT4
ENSG00000255730	ENST00000540732.3 link	c.210+9077C>T		intron_variant	Intron 2 of 9	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

AF:

0.0000987

AC:

AN:

151954

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.000263

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:

0.0000441

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000167

AC:

AN:

221372

Hom.:

AF XY:

0.000218

AC XY:

AN XY:

119368

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000297

Gnomad ASJ exome

AF:

0.000109

Gnomad EAS exome

AF:

0.0000604

Gnomad SAS exome

AF:

0.000335

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000150

Gnomad OTH exome

AF:

0.000367

GnomAD4 exome

AF:

0.000131

AC:

190

AN:

1445332

Hom.:

Cov.:

AF XY:

0.000130

AC XY:

AN XY:

717734

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000387

Gnomad4 ASJ exome

AF:

0.0000392

Gnomad4 EAS exome

AF:

0.0000511

Gnomad4 SAS exome

AF:

0.000457

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000941

Gnomad4 OTH exome

AF:

0.000335

GnomAD4 genome

AF:

0.0000987

AC:

AN:

151954

Hom.:

Cov.:

AF XY:

0.000148

AC XY:

AN XY:

74200

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.000263

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000958

Alfa

AF:

0.000179

Hom.:

Bravo

AF:

0.000340

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000140

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

EXOSC5: BP4 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.078

T;T

Eigen

Benign

0.083

Eigen_PC

Uncertain

0.23

FATHMM_MKL

Benign

0.73

LIST_S2

Uncertain

0.90

D;D

M_CAP

Benign

0.0065

MetaRNN

Benign

0.034

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.4

L;.

PrimateAI

Benign

0.39

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.10

Sift

Benign

0.11

T;.

Sift4G

Benign

0.28

T;T

Polyphen

0.24

B;.

Vest4

0.31

MutPred

0.38

Gain of methylation at K175 (P = 0.0482);.;

MVP

0.19

MPC

0.24

ClinPred

0.025

GERP RS

5.3

Varity_R

0.27

gMVP

0.57

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

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