NM_005033.3:c.1313C>T

Variant names:

• chr4-121816849-C-T
• rs751255089
• NM_005033.3:c.1313C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005033.3(EXOSC9):​c.1313C>T​(p.Ala438Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000107 in 1,583,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000098 (0 hom.)
• Consequence: EXOSC9 NM_005033.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.361
• Publications: 0 publications found

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]

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

ACMG classification

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=0.07594165).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC9	NM_005033.3	MANE Select	c.1313C>T	p.Ala438Val	missense	Exon 12 of 12	NP_005024.2	Q06265-1
	CCNA2	NM_001237.5	MANE Select	c.*789G>A		3_prime_UTR	Exon 8 of 8	NP_001228.2	P20248
	EXOSC9	NM_001034194.2		c.1364C>T	p.Ala455Val	missense	Exon 13 of 13	NP_001029366.1	Q06265-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC9	ENST00000243498.10	TSL:1 MANE Select	c.1313C>T	p.Ala438Val	missense	Exon 12 of 12	ENSP00000243498.5	Q06265-1
	EXOSC9	ENST00000379663.7	TSL:1	c.1364C>T	p.Ala455Val	missense	Exon 13 of 13	ENSP00000368984.3	Q06265-2
	EXOSC9	ENST00000512454.5	TSL:1	c.1265C>T	p.Ala422Val	missense	Exon 11 of 11	ENSP00000425782.1	D6RIY6

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 151982 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000441

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000978 AC: 14 AN: 1432014 Hom.: 0 Cov.: 28 AF XY: 0.00000844 AC XY: 6 AN XY: 711298

African (AFR) AF: 0.00 AC: 0 AN: 31876

American (AMR) AF: 0.00 AC: 0 AN: 41532

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25566

East Asian (EAS) AF: 0.00 AC: 0 AN: 39010

South Asian (SAS) AF: 0.00 AC: 0 AN: 82604

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52282

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5652

European-Non Finnish (NFE) AF: 0.0000110 AC: 12 AN: 1094310

Other (OTH) AF: 0.0000338 AC: 2 AN: 59182

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 151982 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74212

African (AFR) AF: 0.00 AC: 0 AN: 41394

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10556

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 67982

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000227

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0056	T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		0.36
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.43	N
REVEL	Benign	0.058
Sift	Benign	0.10	T
Sift4G	Uncertain	0.033	D
Polyphen		0.0	B
Vest4		0.10
MVP		0.12
MPC		0.063
ClinPred		0.71	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.031
gMVP		0.22
Mutation Taster		=92/8	polymorphism

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

Other links and lift over

dbSNP: rs751255089; hg19: chr4-122738004;