NM_016042.4:c.588T>C

Variant names:

• chr9-37782024-A-G
• rs147568068
• NM_016042.4:c.588T>C

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_016042.4(EXOSC3):​c.588T>C​(p.Asp196Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00111 in 1,614,114 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00063 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (4 hom.)
• Consequence: EXOSC3 NM_016042.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.606
• Publications: 0 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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 9-37782024-A-G is Benign according to our data. Variant chr9-37782024-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 386440.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.606 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.588T>C	p.Asp196Asp	synonymous	Exon 3 of 4	NP_057126.2	Q9NQT5-1
	EXOSC3	NM_001002269.2		c.475-1144T>C		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.588T>C	p.Asp196Asp	synonymous	Exon 3 of 4	ENSP00000323046.4	Q9NQT5-1
	ENSG00000255872	ENST00000540557.1	TSL:5	n.*910+1890T>C		intron	N/A	ENSP00000457548.1
	EXOSC3	ENST00000858037.1		c.588T>C	p.Asp196Asp	synonymous	Exon 3 of 5	ENSP00000528096.1

Frequencies

GnomAD3 genomes AF: 0.000631 AC: 96 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00123

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000469 AC: 118 AN: 251392 AF XY: 0.000420

Gnomad AFR exome AF: 0.000246

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: 0.000985

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.00116 AC: 1702 AN: 1461758 Hom.: 4 Cov.: 30 AF XY: 0.00109 AC XY: 796 AN XY: 727180

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.00149 AC: 1661 AN: 1111940

Other (OTH) AF: 0.000547 AC: 33 AN: 60384

GnomAD4 genome AF: 0.000630 AC: 96 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000604 AC XY: 45 AN XY: 74510

African (AFR) AF: 0.000240 AC: 10 AN: 41594

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00123 AC: 84 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000589 Hom.: 0

Bravo AF: 0.000529

EpiCase AF: 0.000818

EpiControl AF: 0.000889

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EXOSC3-related disorder (1)
-	-	1	Pontocerebellar hypoplasia type 1B (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	3.8
DANN	Benign	0.80
PhyloP100		-0.61
Mutation Taster		=100/0	polymorphism

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: rs147568068; hg19: chr9-37782021;