Genetic Variant EXOSC4:p.Asp245Asn (chr8-144080596-G-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_019037.3(EXOSC4):c.733G>A(p.Asp245Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000009 in 1,444,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

EXOSC4
NM_019037.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.83

Variant links:

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 links:

ENSG00000290230 (HGNC:):

ENSG00000290230 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.1879515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC4	NM_019037.3 link	c.733G>A	p.Asp245Asn	missense_variant	Exon 3 of 3	ENST00000316052.6	NP_061910.1	Q9NPD3
EXOSC4	XM_011517134.4 link	c.439G>A	p.Asp147Asn	missense_variant	Exon 3 of 3		XP_011515436.1
LOC124902038	XR_007061141.1 link	n.1233C>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 link	c.733G>A	p.Asp245Asn	missense_variant	Exon 3 of 3	1	NM_019037.3	ENSP00000315476.4		Q9NPD3
ENSG00000290230	ENST00000703646.1 link	n.705+28G>A		intron_variant	Intron 3 of 7			ENSP00000515414.1		A0A994J4D9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000900

AC:

AN:

1444462

Hom.:

Cov.:

AF XY:

0.00000417

AC XY:

AN XY:

718634

show subpopulations

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000108

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 27, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.733G>A (p.D245N) 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 733, causing the aspartic acid (D) at amino acid position 245 to be replaced by an asparagine (N). 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

0.10

BayesDel_addAF

Benign

-0.058

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.017

Eigen

Benign

-0.12

Eigen_PC

Benign

0.075

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.78

M_CAP

Benign

0.026

MetaRNN

Benign

0.19

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.5

PrimateAI

Uncertain

0.62

PROVEAN

Benign

0.13

REVEL

Benign

0.12

Sift

Uncertain

0.0080

Sift4G

Benign

0.30

Polyphen

0.0060

Vest4

0.34

MutPred

0.43

Gain of MoRF binding (P = 0.0165);

MVP

0.61

MPC

0.45

ClinPred

0.82

GERP RS

5.4

Varity_R

0.24

gMVP

0.45

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over