chr1-11077633-C-T

Position:

• chr1-11077633-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001001998.3(EXOSC10):​c.1768G>A​(p.Val590Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXOSC10 NM_001001998.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.67

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]

ACMG classification

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=0.09899506).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXOSC10	NM_001001998.3	c.1768G>A	p.Val590Met	missense_variant	15/25	ENST00000376936.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXOSC10	ENST00000376936.9	c.1768G>A	p.Val590Met	missense_variant	15/25	1	NM_001001998.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 13, 2023

The c.1768G>A (p.V590M) alteration is located in exon 15 (coding exon 15) of the EXOSC10 gene. This alteration results from a G to A substitution at nucleotide position 1768, causing the valine (V) at amino acid position 590 to be replaced by a methionine (M). 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	0.080
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	17
DANN	Uncertain	0.99
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.099	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.54	N;N;N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.49	N;N
REVEL	Benign	0.012
Sift	Benign	0.12	T;T
Sift4G	Benign	0.18	T;T
Polyphen		0.018	B;B
Vest4		0.25
MutPred		0.35		Loss of methylation at K591 (P = 0.0211);Loss of methylation at K591 (P = 0.0211);
MVP		0.44
MPC		0.22
ClinPred		0.25	T
GERP RS		3.0
Varity_R		0.042
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-11137690;