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

Variant summary

Our verdict is Uncertain significance. The variant received 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

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 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;

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>T	p.Ala2Val	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>T	p.Ala2Val	missense	Exon 1 of 3	ENSP00000315476.4	Q9NPD3
ENSG00000290230	ENST00000703646.1		n.5C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000515414.1	A0A994J4D9
EXOSC4	ENST00000917256.1		c.5C>T	p.Ala2Val	missense	Exon 1 of 3	ENSP00000587315.1

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

GnomAD2 exomes

AF:

0.0000111

AC:

AN:

89920

AF XY:

0.0000204

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000253

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000998

AC:

AN:

1302908

Hom.:

Cov.:

AF XY:

0.0000173

AC XY:

AN XY:

636550

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26590

American (AMR)

AF:

0.0000454

AC:

AN:

22030

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19554

East Asian (EAS)

AF:

0.0000328

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:

0.00000581

AC:

AN:

1032782

Other (OTH)

AF:

0.0000934

AC:

AN:

53524

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.513

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152188

Hom.:

Cov.:

AF XY:

0.0000135

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:

0.0000441

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

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

Alfa

AF:

0.0000367

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000343

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Uncertain

0.046

BayesDel_noAF

Benign

-0.17

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.064

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.22

FATHMM_MKL

Benign

0.62

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.35

MetaRNN

Uncertain

0.47

MetaSVM

Benign

-0.55

MutationAssessor

Benign

1.8

PhyloP100

4.8

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-2.2

REVEL

Uncertain

0.34

Sift

Uncertain

0.021

Sift4G

Uncertain

0.053

Polyphen

1.0

Vest4

0.66

MutPred

0.26

Loss of disorder (P = 0.0939)

MVP

0.73

MPC

1.2

ClinPred

0.86

GERP RS

3.4

PromoterAI

-0.25

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.22

gMVP

0.46

Mutation Taster

=75/25

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over