rs138169215

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2

The NM_016042.4(EXOSC3):c.328G>A(p.Val110Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000739 in 1,605,264 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00072 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00074 ( 3 hom. )

Consequence

EXOSC3
NM_016042.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 7.77

Publications

4 publications found

Variant links:

Genes affected

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

EXOSC3 Gene-Disease associations (from GenCC):

pontocerebellar hypoplasia type 1B
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
pontocerebellar hypoplasia type 1
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

EXOSC3 links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.08224648).

BP6

Variant 9-37784060-C-T is Benign according to our data. Variant chr9-37784060-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 210964.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016042.4. 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
	EXOSC3	NM_016042.4	MANE Select	c.328G>A	p.Val110Ile	missense	Exon 2 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.328G>A	p.Val110Ile	missense	Exon 2 of 3	NP_001002269.1	Q9NQT5-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC3	ENST00000327304.10	TSL:1 MANE Select	c.328G>A	p.Val110Ile	missense	Exon 2 of 4	ENSP00000323046.4	Q9NQT5-1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*764G>A		non_coding_transcript_exon	Exon 9 of 12	ENSP00000457548.1
ENSG00000255872	ENST00000540557.1	TSL:5	n.*764G>A		3_prime_UTR	Exon 9 of 12	ENSP00000457548.1

Frequencies

GnomAD3 genomes

AF:

0.000723

AC:

110

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000145

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00275

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:

0.000897

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000503

AC:

122

AN:

242338

AF XY:

0.000534

show subpopulations

Gnomad AFR exome

AF:

0.000126

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000929

Gnomad OTH exome

AF:

0.000511

GnomAD4 exome

AF:

0.000741

AC:

1077

AN:

1452996

Hom.:

Cov.:

AF XY:

0.000726

AC XY:

525

AN XY:

722660

show subpopulations

African (AFR)

AF:

0.0000913

AC:

AN:

32862

American (AMR)

AF:

0.000513

AC:

AN:

42844

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25842

East Asian (EAS)

AF:

0.00

AC:

AN:

39366

South Asian (SAS)

AF:

0.00

AC:

AN:

84354

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53118

Middle Eastern (MID)

AF:

0.000174

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.000908

AC:

1007

AN:

1108904

Other (OTH)

AF:

0.000734

AC:

AN:

59974

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.459

Heterozygous variant carriers

100

151

201

251

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

160

200

<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:

0.000722

AC:

110

AN:

152268

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.000144

AC:

AN:

41554

American (AMR)

AF:

0.00275

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10602

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000897

AC:

AN:

68016

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.000804

Hom.:

Bravo

AF:

0.000642

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00156

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00151

AC:

ExAC

AF:

0.000453

AC:

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Pontocerebellar hypoplasia type 1B (2)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

M_CAP

Benign

0.014

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.82

PhyloP100

7.8

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.59

REVEL

Benign

0.16

Sift

Benign

0.18

Sift4G

Benign

0.34

Polyphen

0.73

Vest4

0.63

MVP

0.42

MPC

0.49

ClinPred

0.087

GERP RS

5.3

Varity_R

0.28

gMVP

0.24

Mutation Taster

=88/12

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