chr16-70251161-C-G

Variant names:

• chr16-70251161-C-G
• NM_058219.3:c.740G>C

Variant summary

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

The NM_058219.3(EXOSC6):​c.740G>C​(p.Gly247Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000726 in 1,377,674 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: EXOSC6 NM_058219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.85
• 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.740G>C	p.Gly247Ala	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.740G>C	p.Gly247Ala	missense	Exon 1 of 1	ENSP00000398597.1	Q5RKV6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.26e-7 AC: 1 AN: 1377674 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 682364

African (AFR) AF: 0.00 AC: 0 AN: 28560

American (AMR) AF: 0.00 AC: 0 AN: 35838

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24380

East Asian (EAS) AF: 0.0000301 AC: 1 AN: 33172

South Asian (SAS) AF: 0.00 AC: 0 AN: 78956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4348

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1080346

Other (OTH) AF: 0.00 AC: 0 AN: 57382

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Uncertain	0.047	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.080	T
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.78	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Uncertain	-0.076	T
MutationAssessor	Benign	1.3	L
PhyloP100		2.8
PrimateAI	Pathogenic	0.90	D
PROVEAN	Uncertain	-3.0	D
REVEL	Uncertain	0.56
Sift	Benign	0.48	T
Sift4G	Benign	0.36	T
Polyphen		1.0	D
Vest4		0.43
MutPred		0.50		Gain of MoRF binding (P = 0.1045)
MVP		0.91
MPC		1.6
ClinPred		0.98	D
GERP RS		4.0
Varity_R		0.75
gMVP		0.67

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

hg19: chr16-70285064;