Genetic Variant EXOSC4:p.Gly244Gly (chr8-144080595-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS2

The NM_019037.3(EXOSC4):c.732G>A(p.Gly244Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 1,596,730 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0010 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0019 ( 2 hom. )

Consequence

EXOSC4
NM_019037.3 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.24

Publications

2 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: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.65).

BP6

Variant 8-144080595-G-A is Benign according to our data. Variant chr8-144080595-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 3511019.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.24 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

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.732G>A	p.Gly244Gly	synonymous	Exon 3 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.732G>A	p.Gly244Gly	synonymous	Exon 3 of 3	ENSP00000315476.4	Q9NPD3
ENSG00000290230	ENST00000703646.1		n.705+27G>A		intron	N/A	ENSP00000515414.1	A0A994J4D9
EXOSC4	ENST00000917256.1		c.882G>A	p.Gly294Gly	synonymous	Exon 3 of 3	ENSP00000587315.1

Frequencies

GnomAD3 genomes

AF:

0.00103

AC:

157

AN:

152100

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000459

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000524

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00169

Gnomad OTH

AF:

0.000962

GnomAD2 exomes

AF:

0.00123

AC:

294

AN:

238458

AF XY:

0.00135

show subpopulations

Gnomad AFR exome

AF:

0.000127

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000851

Gnomad NFE exome

AF:

0.00191

Gnomad OTH exome

AF:

0.00133

GnomAD4 exome

AF:

0.00193

AC:

2791

AN:

1444512

Hom.:

Cov.:

AF XY:

0.00191

AC XY:

1373

AN XY:

718656

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33436

American (AMR)

AF:

0.000761

AC:

AN:

44692

Ashkenazi Jewish (ASJ)

AF:

0.0000384

AC:

AN:

26064

East Asian (EAS)

AF:

0.00

AC:

AN:

39654

South Asian (SAS)

AF:

0.00154

AC:

133

AN:

86176

European-Finnish (FIN)

AF:

0.000103

AC:

AN:

38774

Middle Eastern (MID)

AF:

0.00472

AC:

AN:

5090

European-Non Finnish (NFE)

AF:

0.00225

AC:

2500

AN:

1110480

Other (OTH)

AF:

0.00141

AC:

AN:

60146

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

173

346

518

691

864

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

200

300

400

500

<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:

0.00104

AC:

158

AN:

152218

Hom.:

Cov.:

AF XY:

0.00109

AC XY:

AN XY:

74404

show subpopulations

African (AFR)

AF:

0.000458

AC:

AN:

41526

American (AMR)

AF:

0.000523

AC:

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00228

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0000942

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00169

AC:

115

AN:

68020

Other (OTH)

AF:

0.000951

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

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:

0.000849

Hom.:

Bravo

AF:

0.000948

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00213

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Likely benign

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

BayesDel_noAF

Benign

-0.65

CADD

Benign

7.1

(source)

DANN

Benign

0.76

PhyloP100

1.2

Mutation Taster

=99/1

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over