Variant 1-11076853-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000376936.9(EXOSC10):c.1975A>T(p.Thr659Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000236 in 1,612,596 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

EXOSC10
ENST00000376936.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.32

Variant links:

Genes affected

EXOSC10 (HGNC:9138): (exosome component 10) Enables 3'-5'-exoribonuclease activity. Involved in several processes, including RNA catabolic process; maturation of 5.8S rRNA; and negative regulation of telomere maintenance via telomerase. Located in cytosol; nuclear lumen; and transcriptionally active chromatin. Part of nuclear exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

EXOSC10 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14370555).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXOSC10	NM_001001998.3 linkuse as main transcript	c.1975A>T	p.Thr659Ser	missense_variant	17/25	ENST00000376936.9	NP_001001998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXOSC10	ENST00000376936.9 linkuse as main transcript	c.1975A>T	p.Thr659Ser	missense_variant	17/25	1	NM_001001998.3	ENSP00000366135	P1	Q01780-1
EXOSC10	ENST00000304457.11 linkuse as main transcript	c.1975A>T	p.Thr659Ser	missense_variant	17/24	1		ENSP00000307307		Q01780-2
EXOSC10	ENST00000470611.5 linkuse as main transcript	n.351A>T		non_coding_transcript_exon_variant	4/5	3
EXOSC10	ENST00000474216.5 linkuse as main transcript	n.1212A>T		non_coding_transcript_exon_variant	5/13	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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

GnomAD3 exomes

AF:

0.0000120

AC:

AN:

250740

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135580

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460356

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

726564

show subpopulations

Gnomad4 AFR exome

AF:

0.00

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:

0.0000315

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152240

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

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

May 30, 2023

The c.1975A>T (p.T659S) alteration is located in exon 17 (coding exon 17) of the EXOSC10 gene. This alteration results from a A to T substitution at nucleotide position 1975, causing the threonine (T) at amino acid position 659 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

Benign

0.084

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Benign

0.93

DEOGEN2

Benign

0.16

.;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.23

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.71

T;T

M_CAP

Benign

0.012

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

MutationTaster

Benign

0.99

D;D;D

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.5

N;N

REVEL

Benign

0.045

Sift

Benign

0.18

T;T

Sift4G

Benign

0.36

T;T

Polyphen

0.20

B;B

Vest4

0.18

MVP

0.64

MPC

0.23

ClinPred

0.15

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.096

gMVP

0.36

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