Genetic Variant EXOSC4:p.Ala2Gly (chr8-144078733-C-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1PM2BP4

The NM_019037.3(EXOSC4):c.5C>G(p.Ala2Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,096 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

EXOSC4
NM_019037.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.78

Publications

1 publications found

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 Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

EXOSC4 links:

ENSG00000290230 (HGNC:):

ENSG00000290230 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 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;

BP4

Computational evidence support a benign effect (MetaRNN=0.31234223).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019037.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC4	NM_019037.3	MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 3	NP_061910.1	Q9NPD3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC4	ENST00000316052.6	TSL:1 MANE Select	c.5C>G	p.Ala2Gly	missense	Exon 1 of 3	ENSP00000315476.4	Q9NPD3
ENSG00000290230	ENST00000703646.1		n.5C>G		non_coding_transcript_exon	Exon 1 of 8	ENSP00000515414.1	A0A994J4D9
EXOSC4	ENST00000917256.1		c.5C>G	p.Ala2Gly	missense	Exon 1 of 3	ENSP00000587315.1

Frequencies

GnomAD3 genomes

AF:

0.00000657

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000154

AC:

AN:

1302908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

636550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26590

American (AMR)

AF:

0.00

AC:

AN:

22030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19554

East Asian (EAS)

AF:

0.00

AC:

AN:

30486

South Asian (SAS)

AF:

0.00

AC:

AN:

66798

European-Finnish (FIN)

AF:

0.00

AC:

AN:

46002

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5142

European-Non Finnish (NFE)

AF:

0.00000194

AC:

AN:

1032782

Other (OTH)

AF:

0.00

AC:

AN:

53524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41450

American (AMR)

AF:

0.00

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.034

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.064

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.12

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.85

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.31

MetaSVM

Benign

-0.89

MutationAssessor

Benign

1.8

PhyloP100

4.8

PrimateAI

Pathogenic

0.83

PROVEAN

Benign

-1.8

REVEL

Benign

0.26

Sift

Benign

0.047

Sift4G

Benign

0.078

Polyphen

0.15

Vest4

0.60

MutPred

0.23

Gain of disorder (P = 0.1047)

MVP

0.70

MPC

0.52

ClinPred

0.82

GERP RS

3.4

PromoterAI

-0.42

Neutral

(source)

Varity_R

0.24

gMVP

0.35

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.12

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over