4-121816810-G-A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005033.3(EXOSC9):c.1274G>A(p.Ser425Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000069 in 1,449,978 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S425T) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

EXOSC9
NM_005033.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.552

Publications

0 publications found

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:

CCNA2 (HGNC:1578): (cyclin A2) The protein encoded by this gene belongs to the highly conserved cyclin family, whose members function as regulators of the cell cycle. This protein binds and activates cyclin-dependent kinase 2 and thus promotes transition through G1/S and G2/M. [provided by RefSeq, Aug 2016]

CCNA2 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: AR Classification: LIMITED Submitted by: G2P

CCNA2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08385244).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005033.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC9	NM_005033.3	MANE Select	c.1274G>A	p.Ser425Asn	missense	Exon 12 of 12	NP_005024.2	Q06265-1
CCNA2	NM_001237.5	MANE Select	c.*828C>T		3_prime_UTR	Exon 8 of 8	NP_001228.2	P20248
EXOSC9	NM_001034194.2		c.1325G>A	p.Ser442Asn	missense	Exon 13 of 13	NP_001029366.1	Q06265-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.1274G>A	p.Ser425Asn	missense	Exon 12 of 12	ENSP00000243498.5	Q06265-1
EXOSC9	ENST00000379663.7	TSL:1	c.1325G>A	p.Ser442Asn	missense	Exon 13 of 13	ENSP00000368984.3	Q06265-2
EXOSC9	ENST00000512454.5	TSL:1	c.1226G>A	p.Ser409Asn	missense	Exon 11 of 11	ENSP00000425782.1	D6RIY6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.90e-7

AC:

AN:

1449978

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

720824

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

32660

American (AMR)

AF:

0.00

AC:

AN:

43346

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25868

East Asian (EAS)

AF:

0.00

AC:

AN:

39416

South Asian (SAS)

AF:

0.00

AC:

AN:

84612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52896

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

9.04e-7

AC:

AN:

1105592

Other (OTH)

AF:

0.00

AC:

AN:

59850

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0050

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.22

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.51

M_CAP

Benign

0.0072

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.55

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.61

REVEL

Benign

0.027

Sift

Benign

0.15

Sift4G

Benign

1.0

Polyphen

0.079

Vest4

0.14

MutPred

0.18

Loss of glycosylation at P424 (P = 0.0061)

MVP

0.12

MPC

0.060

ClinPred

0.42

GERP RS

4.1

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

2.8

Varity_R

0.046

gMVP

0.13

Mutation Taster

=97/3

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over