16-70251323-G-A

Variant names:

• chr16-70251323-G-A
• rs900213082
• NM_058219.3:c.578C>T

Variant summary

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

The NM_058219.3(EXOSC6):​c.578C>T​(p.Pro193Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000812 in 1,231,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 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. P193R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 8.1e-7 (0 hom.)
• Consequence: EXOSC6 NM_058219.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.875
• Publications: 0 publications found

Genes affected

EXOSC6 (HGNC:19055): (exosome component 6) This gene product constitutes one of the subunits of the multisubunit particle called exosome, which mediates mRNA degradation. The composition of human exosome is similar to its yeast counterpart. This protein is homologous to the yeast Mtr3 protein. Its exact function is not known, however, it has been shown using a cell-free RNA decay system that the exosome is required for rapid degradation of unstable mRNAs containing AU-rich elements (AREs), but not for poly(A) shortening. The exosome does not recognize ARE-containing mRNAs on its own, but requires ARE-binding proteins that could interact with the exosome and recruit it to unstable mRNAs, thereby promoting their rapid degradation. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_058219.3. 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
	EXOSC6	NM_058219.3	MANE Select	c.578C>T	p.Pro193Leu	missense	Exon 1 of 1	NP_478126.1	Q5RKV6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC6	ENST00000435634.3	TSL:6 MANE Select	c.578C>T	p.Pro193Leu	missense	Exon 1 of 1	ENSP00000398597.1	Q5RKV6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 8.12e-7 AC: 1 AN: 1231400 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 600600

African (AFR) AF: 0.00 AC: 0 AN: 24496

American (AMR) AF: 0.0000745 AC: 1 AN: 13414

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18290

East Asian (EAS) AF: 0.00 AC: 0 AN: 27382

South Asian (SAS) AF: 0.00 AC: 0 AN: 56210

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3914

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1007102

Other (OTH) AF: 0.00 AC: 0 AN: 50670

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.0085	T
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.55	T
M_CAP	Pathogenic	0.92	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.2	L
PhyloP100		0.88
PrimateAI	Pathogenic	0.90	D
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Benign	0.25	T
Sift4G	Benign	0.30	T
Polyphen		0.11	B
Vest4		0.23
MutPred		0.58		Gain of catalytic residue at P193 (P = 0.0032)
MVP		0.91
MPC		1.1
ClinPred		0.28	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.057
gMVP		0.29

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: rs900213082; hg19: chr16-70285226;