chr13-72761466-C-A

Variant names:

• chr13-72761466-C-A
• NM_014953.5:c.2567G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014953.5(DIS3):​c.2567G>T​(p.Arg856Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DIS3 NM_014953.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.77
• Publications: 0 publications found

Genes affected

DIS3 (HGNC:20604): (DIS3 homolog, exosome endoribonuclease and 3'-5' exoribonuclease) Enables 3'-5'-exoribonuclease activity; endonuclease activity; and guanyl-nucleotide exchange factor activity. Involved in CUT catabolic process and rRNA catabolic process. Located in cytosol and nucleoplasm. Part of nuclear exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014953.5. 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
	DIS3	NM_014953.5	MANE Select	c.2567G>T	p.Arg856Ile	missense	Exon 19 of 21	NP_055768.3
	DIS3	NM_001128226.3		c.2477G>T	p.Arg826Ile	missense	Exon 19 of 21	NP_001121698.1	Q9Y2L1-2
	DIS3	NM_001322348.2		c.2198G>T	p.Arg733Ile	missense	Exon 18 of 20	NP_001309277.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIS3	ENST00000377767.9	TSL:1 MANE Select	c.2567G>T	p.Arg856Ile	missense	Exon 19 of 21	ENSP00000366997.4	Q9Y2L1-1
	DIS3	ENST00000377780.8	TSL:1	c.2477G>T	p.Arg826Ile	missense	Exon 19 of 21	ENSP00000367011.4	Q9Y2L1-2
	DIS3	ENST00000545453.5	TSL:1	c.2081G>T	p.Arg694Ile	missense	Exon 20 of 23	ENSP00000440058.1	G3V1J5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.030
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-0.74	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		4.8
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Uncertain	0.30
Sift	Uncertain	0.010	D
Sift4G	Benign	0.065	T
Polyphen		1.0	D
Vest4		0.70
MutPred		0.64		Gain of catalytic residue at N858 (P = 0.0089)
MVP		0.43
MPC		0.81
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.76
gMVP		0.79
Mutation Taster		=22/78	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

hg19: chr13-73335604;