4-121816818-CCAGTGAAAAGAAGAAAAAAGA-C

Position:

• chr4-121816818-CCAGTGAAAAGAAGAAAAAAGA-C

Variant summary

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

The NM_005033.3(EXOSC9):​c.1283_1303del​(p.Pro428_Lys435delinsGln) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000207 in 1,447,958 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXOSC9 NM_005033.3 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.00

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]

ACMG classification

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	c.1283_1303del	p.Pro428_Lys435delinsGln	inframe_deletion	12/12	ENST00000243498.10	NP_005024.2
CCNA2	NM_001237.5	c.*799_*819del		3_prime_UTR_variant	8/8	ENST00000274026.10	NP_001228.2
EXOSC9	NM_001034194.2	c.1334_1354del	p.Pro445_Lys452delinsGln	inframe_deletion	13/13		NP_001029366.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC9	ENST00000243498.10	c.1283_1303del	p.Pro428_Lys435delinsGln	inframe_deletion	12/12	1	NM_005033.3	ENSP00000243498	P1
CCNA2	ENST00000274026.10	c.*799_*819del		3_prime_UTR_variant	8/8	1	NM_001237.5	ENSP00000274026	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447958 Hom.: 0 AF XY: 0.00000278 AC XY: 2 AN XY: 719830

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

May 10, 2022

This variant, c.1334_1354del, is a complex sequence change that results in the deletion of 8 and insertion of 1 amino acid(s) in the EXOSC9 protein (p.Pro445_Lys452delinsGln). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with EXOSC9-related conditions. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1413221592; hg19: chr4-122737973;