dbSNP rs782335169: EXOSC4:p.Ala2Glu (chr8-144078733-C-A) – 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>A(p.Ala2Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

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 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>A	p.Ala2Glu	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>A	p.Ala2Glu	missense	Exon 1 of 3	ENSP00000315476.4	Q9NPD3
ENSG00000290230	ENST00000703646.1		n.5C>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000515414.1	A0A994J4D9
EXOSC4	ENST00000917256.1		c.5C>A	p.Ala2Glu	missense	Exon 1 of 3	ENSP00000587315.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1302908

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

636550

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:

0.00

AC:

AN:

1032782

Other (OTH)

AF:

0.00

AC:

AN:

53524

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000367

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.50

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Uncertain

0.010

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.062

Eigen

Benign

-0.068

Eigen_PC

Benign

0.028

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.45

MetaSVM

Benign

-0.87

MutationAssessor

Benign

1.8

PhyloP100

4.8

PrimateAI

Pathogenic

0.87

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.38

Sift

Uncertain

0.0080

Sift4G

Uncertain

0.019

Polyphen

0.65

Vest4

0.76

MutPred

0.25

Gain of disorder (P = 0.0725)

MVP

0.72

MPC

0.75

ClinPred

0.96

GERP RS

3.4

PromoterAI

-0.31

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.34

gMVP

0.50

Mutation Taster

=75/25

polymorphism

(source)

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

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over