rs138169215

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM1BP4_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

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 links:

ENSG00000255872 (HGNC:):

ENSG00000255872 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -5 ACMG points.

PM1

In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_016042.4

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 id is 210964.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4 link	c.328G>A	p.Val110Ile	missense_variant	Exon 2 of 4	ENST00000327304.10	NP_057126.2	Q9NQT5-1
EXOSC3	NM_001002269.2 link	c.328G>A	p.Val110Ile	missense_variant	Exon 2 of 3		NP_001002269.1	Q9NQT5-2Q9NYS3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXOSC3	ENST00000327304.10 link	c.328G>A	p.Val110Ile	missense_variant	Exon 2 of 4	1	NM_016042.4	ENSP00000323046.4	Q9NQT5-1
ENSG00000255872	ENST00000540557.1 link	n.*764G>A		non_coding_transcript_exon_variant	Exon 9 of 12	5		ENSP00000457548.1
ENSG00000255872	ENST00000540557.1 link	n.*764G>A		3_prime_UTR_variant	Exon 9 of 12	5		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

GnomAD3 exomes

AF:

0.000503

AC:

122

AN:

242338

Hom.:

AF XY:

0.000534

AC XY:

AN XY:

131138

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 SAS 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

Gnomad4 AFR exome

AF:

0.0000913

Gnomad4 AMR exome

AF:

0.000513

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000908

Gnomad4 OTH exome

AF:

0.000734

GnomAD4 genome

AF:

0.000722

AC:

110

AN:

152268

Hom.:

Cov.:

AF XY:

0.000833

AC XY:

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000144

Gnomad4 AMR

AF:

0.00275

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000897

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000828

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

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia type 1B

Uncertain:1Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Dec 02, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Uncertain:1

Aug 06, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.23

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.010

T;.

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.41

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.93

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.082

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

0.82

L;L

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.16

Sift

Benign

0.18

T;T

Sift4G

Benign

0.34

T;T

Polyphen

0.73

P;.

Vest4

0.63

MVP

0.42

MPC

0.49

ClinPred

0.087

GERP RS

5.3

Varity_R

0.28

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over