rs3208406

chr9-37780834-A-G

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_016042.4(EXOSC3):c.673T>C(p.Tyr225His) variant causes a missense change. The variant allele was found at a frequency of 0.0818 in 1,613,332 control chromosomes in the GnomAD database, including 6,050 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Y225C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.063 (417 hom., cov: 31)
  • Exomes 𝑓: 0.084 (5633 hom.)
• Consequence: EXOSC3 NM_016042.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 6.77

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 -18 ACMG points.

• PM1: In a chain Exosome complex component RRP40 (size 273) in uniprot entity EXOS3_HUMAN there are 19 pathogenic changes around while only 6 benign (76%) in NM_016042.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.0023806393).
• BP6: Variant 9-37780834-A-G is Benign according to our data. Variant chr9-37780834-A-G is described in ClinVar as [Benign]. Clinvar id is 129026.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0918 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC3	NM_016042.4	c.673T>C	p.Tyr225His	missense_variant	4/4	ENST00000327304.10
EXOSC3	NM_001002269.2	c.*26T>C		3_prime_UTR_variant	3/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC3	ENST00000327304.10	c.673T>C	p.Tyr225His	missense_variant	4/4	1	NM_016042.4	P1

Frequencies

GnomAD3 genomes AF: 0.0634 AC: 9643 AN: 152194 Hom.: 418 Cov.: 31

Gnomad AFR AF: 0.0156

Gnomad AMI AF: 0.0779

Gnomad AMR AF: 0.0585

Gnomad ASJ AF: 0.0801

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0370

Gnomad FIN AF: 0.0950

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.0716

GnomAD3 exomes AF: 0.0665 AC: 16702 AN: 250994 Hom.: 717 AF XY: 0.0681 AC XY: 9244 AN XY: 135706

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.0419

Gnomad ASJ exome AF: 0.0748

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0385

Gnomad FIN exome AF: 0.0960

Gnomad NFE exome AF: 0.0935

Gnomad OTH exome AF: 0.0686

GnomAD4 exome AF: 0.0837 AC: 122322 AN: 1461020 Hom.: 5633 Cov.: 31 AF XY: 0.0827 AC XY: 60137 AN XY: 726848

Gnomad4 AFR exome AF: 0.0130

Gnomad4 AMR exome AF: 0.0439

Gnomad4 ASJ exome AF: 0.0791

Gnomad4 EAS exome AF: 0.000328

Gnomad4 SAS exome AF: 0.0402

Gnomad4 FIN exome AF: 0.0931

Gnomad4 NFE exome AF: 0.0938

Gnomad4 OTH exome AF: 0.0790

GnomAD4 genome AF: 0.0632 AC: 9631 AN: 152312 Hom.: 417 Cov.: 31 AF XY: 0.0633 AC XY: 4711 AN XY: 74474

Gnomad4 AFR AF: 0.0155

Gnomad4 AMR AF: 0.0584

Gnomad4 ASJ AF: 0.0801

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0364

Gnomad4 FIN AF: 0.0950

Gnomad4 NFE AF: 0.0937

Gnomad4 OTH AF: 0.0709

Alfa AF: 0.0825 Hom.: 795

Bravo AF: 0.0580

TwinsUK AF: 0.0866 AC: 321

ALSPAC AF: 0.0885 AC: 341

ESP6500AA AF: 0.0202 AC: 89

ESP6500EA AF: 0.0986 AC: 848

ExAC AF: 0.0663 AC: 8053

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0991

EpiControl AF: 0.0968

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 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. -
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. -

Pontocerebellar hypoplasia type 1B Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.47
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.51
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.7	L
MutationTaster	Benign	0.0050	P;P
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.11
Sift	Benign	0.15	T
Sift4G	Benign	0.35	T
Polyphen		0.99	D
Vest4		0.17
MPC		0.63
ClinPred		0.015	T
GERP RS		5.7
Varity_R		0.51
gMVP		0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3208406; hg19: chr9-37780831; COSMIC: COSV53051969; COSMIC: COSV53051969;