chr1-11073948-T-C

Variant names:

• chr1-11073948-T-C
• rs115976717
• NM_001001998.3:c.2143A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001001998.3(EXOSC10):​c.2143A>G​(p.Thr715Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0033 in 1,612,758 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (3 hom., cov: 30)
  • Exomes 𝑓: 0.0034 (18 hom.)
• Consequence: EXOSC10 NM_001001998.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.33
• Publications: 2 publications found

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-AS1 (HGNC:40456): (EXOSC10 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009223729).
• BP6: Variant 1-11073948-T-C is Benign according to our data. Variant chr1-11073948-T-C is described in ClinVar as Likely_benign. ClinVar VariationId is 2638218.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001998.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC10	NM_001001998.3	MANE Select	c.2143A>G	p.Thr715Ala	missense	Exon 19 of 25	NP_001001998.1	Q01780-1
	EXOSC10	NM_002685.4		c.2082+283A>G		intron	N/A	NP_002676.1	Q01780-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXOSC10	ENST00000376936.9	TSL:1 MANE Select	c.2143A>G	p.Thr715Ala	missense	Exon 19 of 25	ENSP00000366135.4	Q01780-1
	EXOSC10	ENST00000304457.11	TSL:1	c.2082+283A>G		intron	N/A	ENSP00000307307.7	Q01780-2
	EXOSC10	ENST00000921096.1		c.2188A>G	p.Thr730Ala	missense	Exon 19 of 25	ENSP00000591155.1

Frequencies

GnomAD3 genomes AF: 0.00215 AC: 326 AN: 151400 Hom.: 3 Cov.: 30

Gnomad AFR AF: 0.000657

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00171

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.000192

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00289

GnomAD2 exomes AF: 0.00179 AC: 451 AN: 251452 AF XY: 0.00189

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000185

Gnomad NFE exome AF: 0.00302

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00343 AC: 5005 AN: 1461286 Hom.: 18 Cov.: 35 AF XY: 0.00339 AC XY: 2462 AN XY: 726998

African (AFR) AF: 0.000777 AC: 26 AN: 33474

American (AMR) AF: 0.00206 AC: 92 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.000612 AC: 16 AN: 26126

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.000209 AC: 18 AN: 86250

European-Finnish (FIN) AF: 0.000225 AC: 12 AN: 53416

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.00416 AC: 4624 AN: 1111466

Other (OTH) AF: 0.00353 AC: 213 AN: 60374

GnomAD4 genome AF: 0.00215 AC: 325 AN: 151472 Hom.: 3 Cov.: 30 AF XY: 0.00184 AC XY: 136 AN XY: 73944

African (AFR) AF: 0.000655 AC: 27 AN: 41204

American (AMR) AF: 0.00171 AC: 26 AN: 15202

Ashkenazi Jewish (ASJ) AF: 0.000866 AC: 3 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5152

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4786

European-Finnish (FIN) AF: 0.000192 AC: 2 AN: 10404

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00381 AC: 259 AN: 67968

Other (OTH) AF: 0.00287 AC: 6 AN: 2094

Alfa AF: 0.00223 Hom.: 1

Bravo AF: 0.00228

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.00157 AC: 191

EpiCase AF: 0.00403

EpiControl AF: 0.00367

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.0041	T
MetaRNN	Benign	0.0092	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		4.3
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.56	N
REVEL	Benign	0.052
Sift	Benign	0.091	T
Sift4G	Benign	0.36	T
Polyphen		0.0090	B
Vest4		0.21
MVP		0.53
MPC		0.22
ClinPred		0.0086	T
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.076
gMVP		0.22
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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

Other links and lift over

dbSNP: rs115976717; hg19: chr1-11134005; COSMIC: COSV100443074; COSMIC: COSV100443074;