rs387907196

Variant names:

• chr9-37784953-C-G
• rs387907196
• NM_016042.4:c.92G>C

Your query was ambiguous. Multiple possible variants found:

• chr9-37784953-C-G
• chr9-37784953-C-A

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PS3 PM2 PP5_Very_Strong

The NM_016042.4(EXOSC3):​c.92G>C​(p.Gly31Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000123 in 1,460,562 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV002238472: Experimental studies have shown that this missense change affects EXOSC3 function (PMID:22544365, 28053271)." and additional evidence is available in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: EXOSC3 NM_016042.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:23 O:1
• Conservation: PhyloP100: 4.47
• Publications: 37 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: Pathogenic. The variant received 14 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV002238472: Experimental studies have shown that this missense change affects EXOSC3 function (PMID: 22544365, 28053271).; SCV004013766: "Functional studies provide supporting evidence of the variant having a damaging effect on the gene or gene product (PMID: 22544365)."; SCV001801416: Published yeast functional studies demonstrate a damaging effect with impaired pre-rRNA processing (Gillespie et al., 2017); PMID: 30986545, 27777260, 27876572, 23883322, 28053271, 29096039, 22544365, 30221345, 30025162, 29656927, 34426522, 31589614, 31770597, 24524299
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-37784953-C-G is Pathogenic according to our data. Variant chr9-37784953-C-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 31691.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.92G>C	p.Gly31Ala	missense	Exon 1 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.92G>C	p.Gly31Ala	missense	Exon 1 of 3	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.92G>C	p.Gly31Ala	missense	Exon 1 of 4	ENSP00000323046.4	Q9NQT5-1
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*761-890G>C		intron	N/A	ENSP00000457548.1
	EXOSC3	ENST00000858037.1		c.92G>C	p.Gly31Ala	missense	Exon 1 of 5	ENSP00000528096.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000204 AC: 5 AN: 244798 AF XY: 0.0000150

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000365

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000123 AC: 18 AN: 1460562 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 726582

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86052

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52846

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111692

Other (OTH) AF: 0.0000663 AC: 4 AN: 60326

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
17	-	-	Pontocerebellar hypoplasia type 1B (18)
4	-	-	not provided (4)
1	-	-	Congenital myopathy (1)
1	-	-	Lissencephaly;C1276035:Fetal akinesia deformation sequence 1;C1848529:Hypoplasia of the pons;C1855843:Severe intrauterine growth retardation;C1866129:Abnormal cerebellum morphology;C2673351:Paucity of anterior horn motor neurons;C4551563:Microcephaly (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.5
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.74
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.51
MutPred		0.42		Loss of loop (P = 0.0073)
MVP		0.89
MPC		0.62
ClinPred		0.98	D
GERP RS		5.3
PromoterAI		-0.10	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.89
gMVP		0.93
Mutation Taster		=3/97	disease causing (ClinVar)

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: rs387907196; hg19: chr9-37784950;