13-37000818-T-C

Position:

chr13-37000818-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBP6

The NM_181503.3(EXOSC8):c.13T>C(p.Phe5Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000557 in 1,578,816 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 Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Uncertain significancein ClinVar.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000056 ( 0 hom. )

Consequence

EXOSC8
NM_181503.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 4.96

Variant links:

Genes affected

EXOSC8 (HGNC:17035): (exosome component 8) This gene encodes a 3'-5' exoribonuclease that specifically interacts with mRNAs containing AU-rich elements. The encoded protein is part of the exosome complex that is important for the degradation of numerous RNA species. A pseudogene of this gene is found on chromosome 6. [provided by RefSeq, Mar 2009]

EXOSC8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14106706).

BP6

Variant 13-37000818-T-C is Benign according to our data. Variant chr13-37000818-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1027899.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC8	NM_181503.3 linkuse as main transcript	c.13T>C	p.Phe5Leu	missense_variant	1/11	ENST00000389704.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC8	ENST00000389704.4 linkuse as main transcript	c.13T>C	p.Phe5Leu	missense_variant	1/11	1	NM_181503.3	P1

Frequencies

GnomAD3 genomes

AF:

0.0000527

AC:

AN:

151910

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.000625

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000481

GnomAD3 exomes

AF:

0.000145

AC:

AN:

192602

Hom.:

AF XY:

0.000231

AC XY:

AN XY:

103804

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000344

Gnomad ASJ exome

AF:

0.000345

Gnomad EAS exome

AF:

0.0000729

Gnomad SAS exome

AF:

0.000823

Gnomad FIN exome

AF:

0.0000585

Gnomad NFE exome

AF:

0.0000121

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000561

AC:

AN:

1426788

Hom.:

Cov.:

AF XY:

0.0000821

AC XY:

AN XY:

706876

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000250

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000683

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000913

Gnomad4 OTH exome

AF:

0.000119

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152028

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74290

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000195

Gnomad4 SAS

AF:

0.000626

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000476

Alfa

AF:

0.0000673

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.000100

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Pontocerebellar hypoplasia, type 1C

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Baylor Genetics

Nov 16, 2019

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). ClinVar contains an entry for this variant (Variation ID: 1027899). This variant has not been reported in the literature in individuals affected with EXOSC8-related conditions. This variant is present in population databases (rs200881798, gnomAD 0.08%). This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 5 of the EXOSC8 protein (p.Phe5Leu). -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Hadassah Hebrew University Medical Center

Jun 20, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.26

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.81

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.14

MetaSVM

Benign

-0.69

MutationAssessor

Uncertain

2.4

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-4.4

REVEL

Benign

0.28

Sift

Uncertain

0.010

Sift4G

Uncertain

0.020

Polyphen

0.94

Vest4

0.56

MutPred

0.56

Gain of catalytic residue at A3 (P = 0.0047);

MVP

0.48

MPC

0.29

ClinPred

0.53

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.80

gMVP

0.61

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