chr4-121801849-A-G

Position:

chr4-121801849-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005033.3(EXOSC9):c.89A>G(p.Tyr30Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000062 in 1,613,788 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

EXOSC9
NM_005033.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.13

Variant links:

Genes affected

EXOSC9 (HGNC:9137): (exosome component 9) This gene encodes a component of the human exosome, a exoribonuclease complex which processes and degrades RNA in the nucleus and cytoplasm. This component may play a role in mRNA degradation and the polymyositis/scleroderma autoantigen complex. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2011]

EXOSC9 links:

EXOSC9 (HGNC:):

EXOSC9 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC9	NM_005033.3 linkuse as main transcript	c.89A>G	p.Tyr30Cys	missense_variant	2/12	ENST00000243498.10	NP_005024.2	Q06265-1
EXOSC9	NM_001034194.2 linkuse as main transcript	c.89A>G	p.Tyr30Cys	missense_variant	2/13		NP_001029366.1	Q06265-2
EXOSC9	XM_011532035.4 linkuse as main transcript	c.89A>G	p.Tyr30Cys	missense_variant	2/11		XP_011530337.1	B4DXG8
EXOSC9	XR_007057929.1 linkuse as main transcript	n.191A>G		non_coding_transcript_exon_variant	2/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC9	ENST00000243498.10 linkuse as main transcript	c.89A>G	p.Tyr30Cys	missense_variant	2/12	1	NM_005033.3	ENSP00000243498.5		Q06265-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251444

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461568

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727116

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74358

show subpopulations

Gnomad4 AFR

AF:

0.0000482

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 01, 2021

This sequence change replaces tyrosine with cysteine at codon 30 of the EXOSC9 protein (p.Tyr30Cys). The tyrosine residue is highly conserved and there is a large physicochemical difference between tyrosine and cysteine. This variant is present in population databases (rs149738039, ExAC 0.01%). This variant has not been reported in the literature in individuals affected with EXOSC9-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.49

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Uncertain

0.010

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.19

T;.;.;T

Eigen

Pathogenic

0.79

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.065

MetaRNN

Uncertain

0.64

D;D;D;D

MetaSVM

Benign

-0.63

MutationAssessor

Uncertain

2.9

M;M;.;.

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-4.1

D;D;D;D

REVEL

Uncertain

0.42

Sift

Benign

0.043

D;T;T;D

Sift4G

Benign

0.13

T;T;T;T

Polyphen

1.0

D;D;.;D

Vest4

0.87

MVP

0.50

MPC

0.39

ClinPred

0.93

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.52

gMVP

0.65

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