rs1041168637

Variant names:

• chr16-70251253-C-T
• rs1041168637
• NM_058219.3:c.648G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-70251253-C-T
• chr16-70251253-C-A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_058219.3(EXOSC6):​c.648G>A​(p.Met216Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000743 in 1,481,340 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000023 (0 hom.)
• Consequence: EXOSC6 NM_058219.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.45
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.41790402).

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.648G>A	p.Met216Ile	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.648G>A	p.Met216Ile	missense	Exon 1 of 1	ENSP00000398597.1	Q5RKV6

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152114 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000226 AC: 3 AN: 1329226 Hom.: 0 Cov.: 29 AF XY: 0.00000153 AC XY: 1 AN XY: 654304

African (AFR) AF: 0.00 AC: 0 AN: 26650

American (AMR) AF: 0.00 AC: 0 AN: 28496

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23240

East Asian (EAS) AF: 0.00 AC: 0 AN: 29860

South Asian (SAS) AF: 0.0000136 AC: 1 AN: 73768

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32922

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4922

European-Non Finnish (NFE) AF: 0.00000190 AC: 2 AN: 1054038

Other (OTH) AF: 0.00 AC: 0 AN: 55330

GnomAD4 genome AF: 0.0000526 AC: 8 AN: 152114 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74316

African (AFR) AF: 0.000169 AC: 7 AN: 41436

American (AMR) AF: 0.00 AC: 0 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000264

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	Pathogenic	0.93
BayesDel_addAF	Benign	-0.014	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.041
Eigen_PC	Benign	-0.014
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.72	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		1.4
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.34
Sift	Uncertain	0.023	D
Sift4G	Benign	0.091	T
Polyphen		0.56	P
Vest4		0.26
MutPred		0.53		Loss of sheet (P = 0.1398)
MVP		0.91
MPC		0.78
ClinPred		0.97	D
GERP RS		3.8
Varity_R		0.81
gMVP		0.35

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1041168637; hg19: chr16-70285156;