Genetic Variant EXOSC4:p.Ala2Val (chr8-144078733-C-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_019037.3(EXOSC4):c.5C>T(p.Ala2Val) variant causes a missense change. The variant allele was found at a frequency of 0.000011 in 1,455,096 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

EXOSC4
NM_019037.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.78

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:

ENSG00000290230 (HGNC:):

ENSG00000290230 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a modified_residue N-acetylalanine (size 0) in uniprot entity EXOS4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC4	NM_019037.3 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 3	ENST00000316052.6	NP_061910.1	Q9NPD3
EXOSC4	XM_011517134.4 link	c.-123-1210C>T		intron_variant	Intron 1 of 2		XP_011515436.1
LOC124902038	XR_007061141.1 link	n.3096G>A		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC4	ENST00000316052.6 link	c.5C>T	p.Ala2Val	missense_variant	Exon 1 of 3	1	NM_019037.3	ENSP00000315476.4		Q9NPD3
ENSG00000290230	ENST00000703646.1 link	n.5C>T		non_coding_transcript_exon_variant	Exon 1 of 8			ENSP00000515414.1		A0A994J4D9

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

GnomAD4 exome

AF:

0.00000998

AC:

AN:

1302908

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

636550

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000454

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000328

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000581

Gnomad4 OTH exome

AF:

0.0000934

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

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:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000343

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Apr 15, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5C>T (p.A2V) alteration is located in exon 1 (coding exon 1) of the EXOSC4 gene. This alteration results from a C to T substitution at nucleotide position 5, causing the alanine (A) at amino acid position 2 to be replaced by a valine (V). 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

0.66

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.064

T;T

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.89

D;D

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.47

T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

L;.

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

N;N

REVEL

Uncertain

0.34

Sift

Uncertain

0.021

D;D

Sift4G

Uncertain

0.053

T;D

Polyphen

1.0

D;.

Vest4

0.66

MutPred

0.26

Loss of disorder (P = 0.0939);Loss of disorder (P = 0.0939);

MVP

0.73

MPC

1.2

ClinPred

0.86

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.22

gMVP

0.46

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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