rs7158

chr9-37782114-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016042.4(EXOSC3):c.498G>A(p.Gln166=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.517 in 1,613,092 control chromosomes in the GnomAD database, including 216,752 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22190 hom., cov: 32)
  • Exomes 𝑓: 0.51 (194562 hom.)
• Consequence: EXOSC3 NM_016042.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.654

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 9-37782114-C-T is Benign according to our data. Variant chr9-37782114-C-T is described in ClinVar as [Benign]. Clinvar id is 129025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-37782114-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.654 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.59 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC3	NM_016042.4	c.498G>A	p.Gln166=	synonymous_variant	3/4	ENST00000327304.10
EXOSC3	NM_001002269.2	c.475-1234G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC3	ENST00000327304.10	c.498G>A	p.Gln166=	synonymous_variant	3/4	1	NM_016042.4	P1

Frequencies

GnomAD3 genomes AF: 0.539 AC: 81882 AN: 151878 Hom.: 22134 Cov.: 32

Gnomad AFR AF: 0.596

Gnomad AMI AF: 0.523

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.433

Gnomad EAS AF: 0.534

Gnomad SAS AF: 0.576

Gnomad FIN AF: 0.568

Gnomad MID AF: 0.404

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.534

GnomAD3 exomes AF: 0.536 AC: 134391 AN: 250866 Hom.: 36469 AF XY: 0.530 AC XY: 71923 AN XY: 135614

Gnomad AFR exome AF: 0.599

Gnomad AMR exome AF: 0.621

Gnomad ASJ exome AF: 0.431

Gnomad EAS exome AF: 0.535

Gnomad SAS exome AF: 0.560

Gnomad FIN exome AF: 0.563

Gnomad NFE exome AF: 0.499

Gnomad OTH exome AF: 0.520

GnomAD4 exome AF: 0.514 AC: 751316 AN: 1461094 Hom.: 194562 Cov.: 44 AF XY: 0.514 AC XY: 373405 AN XY: 726846

Gnomad4 AFR exome AF: 0.597

Gnomad4 AMR exome AF: 0.615

Gnomad4 ASJ exome AF: 0.420

Gnomad4 EAS exome AF: 0.526

Gnomad4 SAS exome AF: 0.555

Gnomad4 FIN exome AF: 0.568

Gnomad4 NFE exome AF: 0.504

Gnomad4 OTH exome AF: 0.514

GnomAD4 genome AF: 0.539 AC: 81993 AN: 151998 Hom.: 22190 Cov.: 32 AF XY: 0.539 AC XY: 40063 AN XY: 74266

Gnomad4 AFR AF: 0.596

Gnomad4 AMR AF: 0.559

Gnomad4 ASJ AF: 0.433

Gnomad4 EAS AF: 0.534

Gnomad4 SAS AF: 0.577

Gnomad4 FIN AF: 0.568

Gnomad4 NFE AF: 0.500

Gnomad4 OTH AF: 0.538

Alfa AF: 0.509 Hom.: 8578

Bravo AF: 0.541

Asia WGS AF: 0.558 AC: 1941 AN: 3478

EpiCase AF: 0.481

EpiControl AF: 0.481

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 08, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Pontocerebellar hypoplasia type 1B Benign:4

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	1.0
Dann	Benign	0.61

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

LitVar

Other links and lift over

dbSNP: rs7158; hg19: chr9-37782111; COSMIC: COSV53050380; COSMIC: COSV53050380;