rs672601331

chr9-37784741-CCCAGTAAACA-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_016042.4(EXOSC3):c.294_303del(p.Val99TrpfsTer11) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,447,360 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. G98G) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: EXOSC3 NM_016042.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 8.83

Genes affected

EXOSC3 (HGNC:17944): (exosome component 3) This gene encodes a non-catalytic component of the human exosome, a complex with 3'-5' exoribonuclease activity that plays a role in numerous RNA processing and degradation activities. Related pseudogenes of this gene are found on chromosome 19 and 21. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jun 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-37784741-CCCAGTAAACA-C is Pathogenic according to our data. Variant chr9-37784741-CCCAGTAAACA-C is described in ClinVar as [Pathogenic]. Clinvar id is 31690.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-37784741-CCCAGTAAACA-C is described in Lovd as [Likely_pathogenic]. Variant chr9-37784741-CCCAGTAAACA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC3	NM_016042.4	c.294_303del	p.Val99TrpfsTer11	frameshift_variant	1/4	ENST00000327304.10
EXOSC3	NM_001002269.2	c.294_303del	p.Val99TrpfsTer11	frameshift_variant	1/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC3	ENST00000327304.10	c.294_303del	p.Val99TrpfsTer11	frameshift_variant	1/4	1	NM_016042.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1447360 Hom.: 0 AF XY: 0.00000139 AC XY: 1 AN XY: 719688

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: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Pontocerebellar hypoplasia type 1B Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 25, 2023	This sequence change creates a premature translational stop signal (p.Val99Trpfs*11) in the EXOSC3 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in EXOSC3 are known to be pathogenic (PMID: 22544365, 23284067, 24524299). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with pontocerebellar hypoplasia (PMID: 22544365). ClinVar contains an entry for this variant (Variation ID: 31690). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 29, 2012	- -

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: rs672601331; hg19: chr9-37784738;