NM_005033.3:c.1318T>G

Variant names:

• chr4-121816854-T-G
• rs547941906
• NM_005033.3:c.1318T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM4 BS1_Supporting

The NM_005033.3(EXOSC9):​c.1318T>G​(p.Ter440Gluext*?) variant causes a stop lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000538 in 1,581,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: EXOSC9 NM_005033.3 stop_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.49
• 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 1 ACMG points.

• PM4: Stoplost variant in NM_005033.3 Downstream stopcodon found after 473 codons.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000348 (53/152248) while in subpopulation AFR AF = 0.00123 (51/41558). AF 95% confidence interval is 0.000958. There are 0 homozygotes in GnomAd4. There are 24 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1318T>G	p.Ter440Gluext*?	stop_lost	Exon 12 of 12	NP_005024.2	Q06265-1
	CCNA2	NM_001237.5	MANE Select	c.*784A>C		3_prime_UTR	Exon 8 of 8	NP_001228.2	P20248
	EXOSC9	NM_001034194.2		c.1369T>G	p.Ter457Gluext*?	stop_lost	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.1318T>G	p.Ter440Gluext*?	stop_lost	Exon 12 of 12	ENSP00000243498.5	Q06265-1
	EXOSC9	ENST00000379663.7	TSL:1	c.1369T>G	p.Ter457Gluext*?	stop_lost	Exon 13 of 13	ENSP00000368984.3	Q06265-2
	EXOSC9	ENST00000512454.5	TSL:1	c.1270T>G	p.Ter424Gluext*?	stop_lost	Exon 11 of 11	ENSP00000425782.1	D6RIY6

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000710 AC: 15 AN: 211194 AF XY: 0.0000613

Gnomad AFR exome AF: 0.00103

Gnomad AMR exome AF: 0.0000654

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000224 AC: 32 AN: 1429142 Hom.: 0 Cov.: 28 AF XY: 0.0000197 AC XY: 14 AN XY: 709846

African (AFR) AF: 0.000789 AC: 25 AN: 31688

American (AMR) AF: 0.000121 AC: 5 AN: 41254

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25484

East Asian (EAS) AF: 0.00 AC: 0 AN: 38958

South Asian (SAS) AF: 0.00 AC: 0 AN: 82324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52236

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5644

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1092538

Other (OTH) AF: 0.0000169 AC: 1 AN: 59016

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152248 Hom.: 0 Cov.: 32 AF XY: 0.000322 AC XY: 24 AN XY: 74436

African (AFR) AF: 0.00123 AC: 51 AN: 41558

American (AMR) AF: 0.000131 AC: 2 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68014

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000548 Hom.: 0

Bravo AF: 0.000423

ExAC AF: 0.000124 AC: 15

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.89
Eigen	Pathogenic	0.85
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.83	D
PhyloP100		3.5
Vest4		0.034
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=139/61	disease causing (ClinVar)

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: rs547941906; hg19: chr4-122738009;