chr9-37780834-A-G

Position:

chr9-37780834-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The ENST00000327304.10(EXOSC3):c.673T>C(p.Tyr225His) variant causes a missense change. The variant allele was found at a frequency of 0.0818 in 1,613,332 control chromosomes in the GnomAD database, including 6,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y225C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.063 ( 417 hom., cov: 31)

Exomes 𝑓: 0.084 ( 5633 hom. )

Consequence

EXOSC3
ENST00000327304.10 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 6.77

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 19 pathogenic changes around while only 7 benign (73%) in ENST00000327304.10

BP4

Computational evidence support a benign effect (MetaRNN=0.0023806393).

BP6

Variant 9-37780834-A-G is Benign according to our data. Variant chr9-37780834-A-G is described in ClinVar as [Benign]. Clinvar id is 129026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC3	NM_016042.4 linkuse as main transcript	c.673T>C	p.Tyr225His	missense_variant	4/4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2 linkuse as main transcript	c.*26T>C		3_prime_UTR_variant	3/3		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10 linkuse as main transcript	c.673T>C	p.Tyr225His	missense_variant	4/4	1	NM_016042.4	ENSP00000323046	P1	Q9NQT5-1

Frequencies

GnomAD3 genomes

AF:

0.0634

AC:

9643

AN:

152194

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0156

Gnomad AMI

AF:

0.0779

Gnomad AMR

AF:

0.0585

Gnomad ASJ

AF:

0.0801

Gnomad EAS

AF:

0.000769

Gnomad SAS

AF:

0.0370

Gnomad FIN

AF:

0.0950

Gnomad MID

AF:

0.108

Gnomad NFE

AF:

0.0938

Gnomad OTH

AF:

0.0716

GnomAD3 exomes

AF:

0.0665

AC:

16702

AN:

250994

Hom.:

717

AF XY:

0.0681

AC XY:

9244

AN XY:

135706

show subpopulations

Gnomad AFR exome

AF:

0.0133

Gnomad AMR exome

AF:

0.0419

Gnomad ASJ exome

AF:

0.0748

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0385

Gnomad FIN exome

AF:

0.0960

Gnomad NFE exome

AF:

0.0935

Gnomad OTH exome

AF:

0.0686

GnomAD4 exome

AF:

0.0837

AC:

122322

AN:

1461020

Hom.:

5633

Cov.:

AF XY:

0.0827

AC XY:

60137

AN XY:

726848

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.0439

Gnomad4 ASJ exome

AF:

0.0791

Gnomad4 EAS exome

AF:

0.000328

Gnomad4 SAS exome

AF:

0.0402

Gnomad4 FIN exome

AF:

0.0931

Gnomad4 NFE exome

AF:

0.0938

Gnomad4 OTH exome

AF:

0.0790

GnomAD4 genome

AF:

0.0632

AC:

9631

AN:

152312

Hom.:

417

Cov.:

AF XY:

0.0633

AC XY:

4711

AN XY:

74474

show subpopulations

Gnomad4 AFR

AF:

0.0155

Gnomad4 AMR

AF:

0.0584

Gnomad4 ASJ

AF:

0.0801

Gnomad4 EAS

AF:

0.000771

Gnomad4 SAS

AF:

0.0364

Gnomad4 FIN

AF:

0.0950

Gnomad4 NFE

AF:

0.0937

Gnomad4 OTH

AF:

0.0709

Alfa

AF:

0.0825

Hom.:

795

Bravo

AF:

0.0580

TwinsUK

AF:

0.0866

AC:

321

ALSPAC

AF:

0.0885

AC:

341

ESP6500AA

AF:

0.0202

AC:

ESP6500EA

AF:

0.0986

AC:

848

ExAC

AF:

0.0663

AC:

8053

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0991

EpiControl

AF:

0.0968

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Pontocerebellar hypoplasia type 1B

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.47

BayesDel_addAF

Benign

-0.56

BayesDel_noAF

Benign

-0.51

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

MutationTaster

Benign

0.0050

P;P

PrimateAI

Uncertain

0.66

PROVEAN

Uncertain

-2.7

REVEL

Benign

0.11

Sift

Benign

0.15

Sift4G

Benign

0.35

Polyphen

0.99

Vest4

0.17

MPC

0.63

ClinPred

0.015

GERP RS

5.7

Varity_R

0.51

gMVP

0.68

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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