rs7158

Variant names:

• chr9-37782114-C-T
• rs7158
• NM_016042.4:c.498G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_016042.4(EXOSC3):​c.498G>A​(p.Gln166Gln) 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:9
• Conservation: PhyloP100: -0.654
• Publications: 21 publications found

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]

EXOSC3 Gene-Disease associations (from GenCC):

• pontocerebellar hypoplasia type 1B

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Illumina
• pontocerebellar hypoplasia type 1

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000255872 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 129025.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
EXOSC3	NM_016042.4	c.498G>A	p.Gln166Gln	synonymous_variant	Exon 3 of 4	ENST00000327304.10	NP_057126.2
EXOSC3	NM_001002269.2	c.475-1234G>A		intron_variant	Intron 2 of 2		NP_001002269.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC3	ENST00000327304.10	c.498G>A	p.Gln166Gln	synonymous_variant	Exon 3 of 4	1	NM_016042.4	ENSP00000323046.4
ENSG00000255872	ENST00000540557.1	n.*910+1800G>A		intron_variant	Intron 9 of 11	5		ENSP00000457548.1

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

GnomAD2 exomes AF: 0.536 AC: 134391 AN: 250866 AF XY: 0.530

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 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

African (AFR) AF: 0.597 AC: 19977 AN: 33460

American (AMR) AF: 0.615 AC: 27506 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.420 AC: 10980 AN: 26122

East Asian (EAS) AF: 0.526 AC: 20890 AN: 39692

South Asian (SAS) AF: 0.555 AC: 47854 AN: 86220

European-Finnish (FIN) AF: 0.568 AC: 30321 AN: 53378

Middle Eastern (MID) AF: 0.424 AC: 2444 AN: 5766

European-Non Finnish (NFE) AF: 0.504 AC: 560326 AN: 1111366

Other (OTH) AF: 0.514 AC: 31018 AN: 60376

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

African (AFR) AF: 0.596 AC: 24715 AN: 41466

American (AMR) AF: 0.559 AC: 8541 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.433 AC: 1501 AN: 3470

East Asian (EAS) AF: 0.534 AC: 2755 AN: 5164

South Asian (SAS) AF: 0.577 AC: 2781 AN: 4820

European-Finnish (FIN) AF: 0.568 AC: 5985 AN: 10536

Middle Eastern (MID) AF: 0.408 AC: 119 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 33984 AN: 67960

Other (OTH) AF: 0.538 AC: 1136 AN: 2110

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:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 08, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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. -

Pontocerebellar hypoplasia type 1B Benign:4

Aug 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
CADD	Benign	1.0
DANN	Benign	0.61
PhyloP100		-0.65
Mutation Taster		=100/0	polymorphism (auto)

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