Variant 8-144080552-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The ENST00000316052.6(EXOSC4):c.689G>A(p.Arg230Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,448,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

EXOSC4
ENST00000316052.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.609

Variant links:

Genes affected

EXOSC4 (HGNC:18189): (exosome component 4) Enables mRNA 3'-UTR AU-rich region binding activity. Involved in nucleic acid metabolic process and positive regulation of cell growth. Acts upstream of or within defense response to virus. Located in cytosol; nucleoplasm; and transcriptionally active chromatin. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC4 links:

LOC124902038 (HGNC:):

LOC124902038 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040620685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
EXOSC4	NM_019037.3 linkuse as main transcript	c.689G>A	p.Arg230Gln	missense_variant	3/3	ENST00000316052.6	NP_061910.1
LOC124902038	XR_007061141.1 linkuse as main transcript	n.1277C>T		non_coding_transcript_exon_variant	2/2
EXOSC4	XM_011517134.4 linkuse as main transcript	c.395G>A	p.Arg132Gln	missense_variant	3/3		XP_011515436.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris
EXOSC4	ENST00000316052.6 linkuse as main transcript	c.689G>A	p.Arg230Gln	missense_variant	3/3	1	NM_019037.3	ENSP00000315476	P1
EXOSC4	ENST00000527954.1 linkuse as main transcript	c.758G>A	p.Arg253Gln	missense_variant	2/2	2		ENSP00000436539
EXOSC4	ENST00000525936.1 linkuse as main transcript			downstream_gene_variant		3		ENSP00000432661

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000552

AC:

AN:

1448458

Hom.:

Cov.:

AF XY:

0.00000555

AC XY:

AN XY:

721040

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:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 20, 2023

The c.689G>A (p.R230Q) alteration is located in exon 3 (coding exon 3) of the EXOSC4 gene. This alteration results from a G to A substitution at nucleotide position 689, causing the arginine (R) at amino acid position 230 to be replaced by a glutamine (Q). 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

Benign

0.070

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.016

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.16

LIST_S2

Uncertain

0.86

D;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.041

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.26

N;.

MutationTaster

Benign

1.0

PrimateAI

Benign

0.32

PROVEAN

Benign

0.42

N;N

REVEL

Benign

0.059

Sift

Benign

0.49

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.0010

B;.

Vest4

0.074

MutPred

0.31

Loss of MoRF binding (P = 0.0152);.;

MVP

0.45

MPC

0.51

ClinPred

0.081

GERP RS

0.33

Varity_R

0.048

gMVP

0.23

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

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