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: Illumina, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016042.4. 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
	EXOSC3	NM_016042.4	MANE Select	c.498G>A	p.Gln166Gln	synonymous	Exon 3 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.475-1234G>A		intron	N/A	NP_001002269.1	Q9NQT5-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC3	ENST00000327304.10	TSL:1 MANE Select	c.498G>A	p.Gln166Gln	synonymous	Exon 3 of 4	ENSP00000323046.4	Q9NQT5-1
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*910+1800G>A		intron	N/A	ENSP00000457548.1
	EXOSC3	ENST00000858037.1		c.498G>A	p.Gln166Gln	synonymous	Exon 3 of 5	ENSP00000528096.1

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

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	4	Pontocerebellar hypoplasia type 1B (4)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

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;