8-144079971-C-G

Position:

• chr8-144079971-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_019037.3(EXOSC4):​c.200C>G​(p.Pro67Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 33)
• Consequence: EXOSC4 NM_019037.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.89

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 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=0.22347608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC4	NM_019037.3	c.200C>G	p.Pro67Arg	missense_variant	2/3	ENST00000316052.6	NP_061910.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC4	ENST00000316052.6	c.200C>G	p.Pro67Arg	missense_variant	2/3	1	NM_019037.3	ENSP00000315476.4
ENSG00000290230	ENST00000703646.1	n.200C>G		non_coding_transcript_exon_variant	2/8			ENSP00000515414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.200C>G (p.P67R) alteration is located in exon 2 (coding exon 2) of the EXOSC4 gene. This alteration results from a C to G substitution at nucleotide position 200, causing the proline (P) at amino acid position 67 to be replaced by an arginine (R). 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	0.27
BayesDel_addAF	Benign	-0.051	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.065	T;T;.
Eigen	Benign	-0.060
Eigen_PC	Benign	0.12
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.91	D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.22	T;T;T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.86	L;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Benign	1.1	N;N;N
REVEL	Benign	0.11
Sift	Benign	0.45	T;D;T
Sift4G	Benign	0.66	T;T;T
Polyphen		0.013	B;.;.
Vest4		0.44
MutPred		0.30		Gain of MoRF binding (P = 0.007);Gain of MoRF binding (P = 0.007);.;
MVP		0.74
MPC		0.49
ClinPred		0.78	D
GERP RS		5.0
Varity_R		0.42
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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.

Other links and lift over

hg19: chr8-145134874; COSMIC: COSV60156183; COSMIC: COSV60156183;