8-144080552-G-A

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_019037.3(EXOSC4):​c.689G>A​(p.Arg230Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000552 in 1,448,458 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: EXOSC4 NM_019037.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.609

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]

ENSG00000290230 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.040620685).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC4	NM_019037.3	c.689G>A	p.Arg230Gln	missense_variant	Exon 3 of 3	ENST00000316052.6	NP_061910.1
EXOSC4	XM_011517134.4	c.395G>A	p.Arg132Gln	missense_variant	Exon 3 of 3		XP_011515436.1
LOC124902038	XR_007061141.1	n.1277C>T		non_coding_transcript_exon_variant	Exon 2 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC4	ENST00000316052.6	c.689G>A	p.Arg230Gln	missense_variant	Exon 3 of 3	1	NM_019037.3	ENSP00000315476.4
ENSG00000290230	ENST00000703646.1	n.689G>A		non_coding_transcript_exon_variant	Exon 3 of 8			ENSP00000515414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000552 AC: 8 AN: 1448458 Hom.: 0 Cov.: 31 AF XY: 0.00000555 AC XY: 4 AN XY: 721040

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 20, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.689G>A (p.R230Q) alteration is located in exon 3 (coding exon 3) of the EXOSC4 gene. This alteration results from a G to A substitution at nucleotide position 689, causing the arginine (R) at amino acid position 230 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	11
DANN	Benign	0.82
DEOGEN2	Benign	0.016	T;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.16	N
LIST_S2	Uncertain	0.86	D;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.041	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.26	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.42	N;N
REVEL	Benign	0.059
Sift	Benign	0.49	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0010	B;.
Vest4		0.074
MutPred		0.31		Loss of MoRF binding (P = 0.0152);.;
MVP		0.45
MPC		0.51
ClinPred		0.081	T
GERP RS		0.33
Varity_R		0.048
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs1217506792; hg19: chr8-145135455; COSMIC: COSV60155506; COSMIC: COSV60155506;