Variant 16-70251399-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_058219.3(EXOSC6):c.502G>T(p.Ala168Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000402 in 1,343,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000041 ( 0 hom. )

Consequence

EXOSC6
NM_058219.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.03

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 made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.913

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC6	NM_058219.3 linkuse as main transcript	c.502G>T	p.Ala168Ser	missense_variant	1/1	ENST00000435634.3	NP_478126.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC6	ENST00000435634.3 linkuse as main transcript	c.502G>T	p.Ala168Ser	missense_variant	1/1		NM_058219.3	ENSP00000398597	P1

Frequencies

GnomAD3 genomes

AF:

0.0000330

AC:

AN:

151292

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

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:

0.0000591

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000108

AC:

AN:

18472

Hom.:

AF XY:

0.000174

AC XY:

AN XY:

11516

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000137

Gnomad OTH exome

AF:

0.00187

GnomAD4 exome

AF:

0.0000411

AC:

AN:

1192430

Hom.:

Cov.:

AF XY:

0.0000361

AC XY:

AN XY:

580982

show subpopulations

Gnomad4 AFR exome

AF:

0.0000421

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000476

Gnomad4 OTH exome

AF:

0.0000206

GnomAD4 genome

AF:

0.0000330

AC:

AN:

151292

Hom.:

Cov.:

AF XY:

0.0000271

AC XY:

AN XY:

73886

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000591

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000491

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.502G>T (p.A168S) alteration is located in exon 1 (coding exon 1) of the EXOSC6 gene. This alteration results from a G to T substitution at nucleotide position 502, causing the alanine (A) at amino acid position 168 to be replaced by a serine (S). 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

Uncertain

0.36

BayesDel_addAF

Uncertain

0.093

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.37

Eigen

Uncertain

0.59

Eigen_PC

Uncertain

0.45

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.76

M_CAP

Pathogenic

0.96

MetaRNN

Pathogenic

0.91

MetaSVM

Pathogenic

0.80

MutationAssessor

Pathogenic

3.4

MutationTaster

Benign

1.0

PrimateAI

Pathogenic

0.94

PROVEAN

Uncertain

-2.8

REVEL

Pathogenic

0.86

Sift

Uncertain

0.012

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.55

MutPred

0.78

Gain of glycosylation at A168 (P = 0.0403);

MVP

0.92

MPC

1.5

ClinPred

0.83

GERP RS

3.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.91

gMVP

0.53

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over