1-11068021-C-T

Variant names:

• chr1-11068021-C-T
• rs1018782839
• NM_001001998.3:c.2614G>A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001001998.3(EXOSC10):​c.2614G>A​(p.Gly872Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,830 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXOSC10 NM_001001998.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.08

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3806006).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC10	NM_001001998.3	c.2614G>A	p.Gly872Arg	missense_variant	Exon 24 of 25	ENST00000376936.9	NP_001001998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC10	ENST00000376936.9	c.2614G>A	p.Gly872Arg	missense_variant	Exon 24 of 25	1	NM_001001998.3	ENSP00000366135.4
EXOSC10	ENST00000304457.11	c.2539G>A	p.Gly847Arg	missense_variant	Exon 23 of 24	1		ENSP00000307307.7
EXOSC10	ENST00000474216.5	n.1866G>A		non_coding_transcript_exon_variant	Exon 12 of 13	2
EXOSC10	ENST00000490565.1	n.344G>A		non_coding_transcript_exon_variant	Exon 2 of 3	2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727212

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 24, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2614G>A (p.G872R) alteration is located in exon 24 (coding exon 24) of the EXOSC10 gene. This alteration results from a G to A substitution at nucleotide position 2614, causing the glycine (G) at amino acid position 872 to be replaced by an arginine (R). 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	0.17
BayesDel_addAF	Benign	0.010	T
BayesDel_noAF	Benign	-0.22
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	.;T
Eigen	Benign	0.11
Eigen_PC	Benign	0.030
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-0.84	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.13	T;T
Polyphen		0.98	D;D
Vest4		0.56
MutPred		0.17		.;Gain of MoRF binding (P = 0.0454);
MVP		0.73
MPC		0.76
ClinPred		0.85	D
GERP RS		4.3
Varity_R		0.068
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1018782839; hg19: chr1-11128078;