Variant chr19-41391872-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_020158.4(EXOSC5):c.353T>C(p.Val118Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,395,298 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

EXOSC5
NM_020158.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.49

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:

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ACMG classification

Classification made for transcript

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
EXOSC5	NM_020158.4 linkuse as main transcript	c.353T>C	p.Val118Ala	missense_variant	3/6	ENST00000221233.9	NP_064543.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC5	ENST00000221233.9 linkuse as main transcript	c.353T>C	p.Val118Ala	missense_variant	3/6	1	NM_020158.4	ENSP00000221233	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000525

AC:

AN:

190452

Hom.:

AF XY:

0.00000949

AC XY:

AN XY:

105324

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000501

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.17e-7

AC:

AN:

1395298

Hom.:

Cov.:

AF XY:

0.00000144

AC XY:

AN XY:

693162

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000337

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 27, 2023

The c.353T>C (p.V118A) alteration is located in exon 3 (coding exon 3) of the EXOSC5 gene. This alteration results from a T to C substitution at nucleotide position 353, causing the valine (V) at amino acid position 118 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.67

BayesDel_addAF

Benign

-0.032

BayesDel_noAF

Benign

-0.14

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

T;T

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.50

FATHMM_MKL

Uncertain

0.97

LIST_S2

Benign

0.84

T;T

M_CAP

Benign

0.056

MetaRNN

Uncertain

0.69

D;D

MetaSVM

Benign

-0.36

MutationAssessor

Uncertain

2.6

M;.

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-3.8

D;.

REVEL

Uncertain

0.42

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

0.87

P;.

Vest4

0.68

MutPred

0.67

Loss of stability (P = 0.0812);.;

MVP

0.81

MPC

0.74

ClinPred

0.95

GERP RS

4.3

Varity_R

0.74

gMVP

0.80

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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