Genetic Variant EXOSC6:p.Leu97Arg (chr16-70251611-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_058219.3(EXOSC6):c.290T>G(p.Leu97Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000108 in 922,470 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. L97H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000011 ( 0 hom. )

Consequence

EXOSC6
NM_058219.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.07

Variant links:

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]

EXOSC6 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.24417457).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC6	NM_058219.3 link	c.290T>G	p.Leu97Arg	missense_variant	Exon 1 of 1	ENST00000435634.3	NP_478126.1	Q5RKV6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC6	ENST00000435634.3 link	c.290T>G	p.Leu97Arg	missense_variant	Exon 1 of 1	6	NM_058219.3	ENSP00000398597.1		Q5RKV6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000108

AC:

AN:

922470

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

432798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

17902

American (AMR)

AF:

0.00

AC:

AN:

3778

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7798

East Asian (EAS)

AF:

0.00

AC:

AN:

9038

South Asian (SAS)

AF:

0.00

AC:

AN:

18210

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9678

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2074

European-Non Finnish (NFE)

AF:

0.00000122

AC:

AN:

821228

Other (OTH)

AF:

0.00

AC:

AN:

32764

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

0.0090

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.041

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.42

M_CAP

Pathogenic

0.53

MetaRNN

Benign

0.24

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.33

PhyloP100

2.1

PrimateAI

Pathogenic

0.94

PROVEAN

Benign

-0.83

REVEL

Benign

0.090

Sift

Benign

0.32

Sift4G

Benign

0.38

Polyphen

0.51

Vest4

0.39

MutPred

0.58

Gain of MoRF binding (P = 0.0201);

MVP

0.35

MPC

0.95

ClinPred

0.46

GERP RS

1.4

PromoterAI

0.057

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.40

gMVP

0.44

Mutation Taster

=63/37

polymorphism

(source)

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

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16-70251611-A-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

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