13-37000818-T-C

Position:

• chr13-37000818-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

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).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000056 (0 hom.)
• Consequence: EXOSC8 NM_181503.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 4.96

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]

ACMG classification

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: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC8	NM_181503.3	c.13T>C	p.Phe5Leu	missense_variant	1/11	ENST00000389704.4	NP_852480.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC8	ENST00000389704.4	c.13T>C	p.Phe5Leu	missense_variant	1/11	1	NM_181503.3	ENSP00000374354	P1

Frequencies

GnomAD3 genomes AF: 0.0000527 AC: 8 AN: 151910 Hom.: 0 Cov.: 33

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: 28 AN: 192602 Hom.: 0 AF XY: 0.000231 AC XY: 24 AN XY: 103804

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: 80 AN: 1426788 Hom.: 0 Cov.: 30 AF XY: 0.0000821 AC XY: 58 AN XY: 706876

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: 8 AN: 152028 Hom.: 0 Cov.: 33 AF XY: 0.0000538 AC XY: 4 AN XY: 74290

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.: 0

Bravo AF: 0.0000340

ExAC AF: 0.000100 AC: 12

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

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

Labcorp Genetics (formerly Invitae), Labcorp

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	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.22	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-0.69	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Benign	0.28
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.020	D
Polyphen		0.94	P
Vest4		0.56
MutPred		0.56		Gain of catalytic residue at A3 (P = 0.0047);
MVP		0.48
MPC		0.29
ClinPred		0.53	D
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

Other links and lift over

dbSNP: rs200881798; hg19: chr13-37574955;