NM_019037.3:c.689G>C

Variant names:

• chr8-144080552-G-C
• rs1217506792
• NM_019037.3:c.689G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019037.3(EXOSC4):​c.689G>C​(p.Arg230Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R230Q) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: EXOSC4 NM_019037.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.609
• Publications: 0 publications found

Genes affected

EXOSC4 (HGNC:18189): (exosome component 4) Enables mRNA 3'-UTR AU-rich region binding activity. Involved in nucleic acid metabolic process and positive regulation of cell growth. Acts upstream of or within defense response to virus. Located in cytosol; nucleoplasm; and transcriptionally active chromatin. Part of exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC4 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ENSG00000290230 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15558529).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019037.3. 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
	EXOSC4	NM_019037.3	MANE Select	c.689G>C	p.Arg230Pro	missense	Exon 3 of 3	NP_061910.1	Q9NPD3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC4	ENST00000316052.6	TSL:1 MANE Select	c.689G>C	p.Arg230Pro	missense	Exon 3 of 3	ENSP00000315476.4	Q9NPD3
	ENSG00000290230	ENST00000703646.1		n.689G>C		non_coding_transcript_exon	Exon 3 of 8	ENSP00000515414.1	A0A994J4D9
	EXOSC4	ENST00000917256.1		c.839G>C	p.Arg280Pro	missense	Exon 3 of 3	ENSP00000587315.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Uncertain	0.041	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	19
DANN	Benign	0.85
DEOGEN2	Benign	0.077	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.93
FATHMM_MKL	Benign	0.38	N
LIST_S2	Uncertain	0.88	D
M_CAP	Benign	0.039	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.61
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Benign	0.10	T
Sift4G	Benign	0.11	T
Polyphen		0.37	B
Vest4		0.56
MutPred		0.41		Loss of MoRF binding (P = 3e-04)
MVP		0.65
MPC		0.79
ClinPred		0.19	T
GERP RS		0.33
Varity_R		0.38
gMVP		0.76
Mutation Taster		=54/46	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: rs1217506792; hg19: chr8-145135455;