NM_001001998.3:c.2504A>C

Variant names:

• chr1-11068691-T-G
• NM_001001998.3:c.2504A>C

Variant summary

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

The NM_001001998.3(EXOSC10):​c.2504A>C​(p.Lys835Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K835R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: EXOSC10 NM_001001998.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.12

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]

ENSG00000226849 (HGNC:):

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=0.20123562).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXOSC10	NM_001001998.3	c.2504A>C	p.Lys835Thr	missense_variant	Exon 23 of 25	ENST00000376936.9	NP_001001998.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXOSC10	ENST00000376936.9	c.2504A>C	p.Lys835Thr	missense_variant	Exon 23 of 25	1	NM_001001998.3	ENSP00000366135.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;T
Eigen	Benign	-0.011
Eigen_PC	Benign	-0.064
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.013	T
MetaRNN	Benign	0.20	T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	.;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.7	N;N
REVEL	Benign	0.27
Sift	Uncertain	0.0040	D;D
Sift4G	Benign	0.084	T;T
Polyphen		0.97	D;D
Vest4		0.22
MutPred		0.19		.;Loss of catalytic residue at K835 (P = 0.0077);
MVP		0.64
MPC		0.27
ClinPred		0.75	D
GERP RS		2.5
Varity_R		0.20
gMVP		0.25

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: chr1-11128748;