Genetic Variant NM_020158.4:c.646G>T (chr19-41386695-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_020158.4(EXOSC5):c.646G>T(p.Ala216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000069 in 1,449,090 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EXOSC5
NM_020158.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.18

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.783

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC5	NM_020158.4 link	c.646G>T	p.Ala216Ser	missense_variant	Exon 6 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.646G>T	p.Ala216Ser	missense_variant	Exon 6 of 6	1	NM_020158.4	ENSP00000221233.3		Q9NQT4
ENSG00000255730	ENST00000540732.3 link	c.210+8176C>A		intron_variant	Intron 2 of 9	2		ENSP00000443246.1		F5H5P2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449090

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

719662

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.03e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.11

T;T

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.70

T;T

M_CAP

Benign

0.019

MetaRNN

Pathogenic

0.78

D;D

MetaSVM

Benign

-0.72

MutationAssessor

Uncertain

2.8

M;.

PrimateAI

Benign

0.44

PROVEAN

Benign

-2.1

N;.

REVEL

Benign

0.29

Sift

Benign

0.042

D;.

Sift4G

Uncertain

0.030

D;D

Polyphen

0.99

D;.

Vest4

0.45

MutPred

0.81

Gain of disorder (P = 0.0273);.;

MVP

0.20

MPC

0.74

ClinPred

0.96

GERP RS

4.0

Varity_R

0.53

gMVP

0.62

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over