13-72761401-T-C

Variant names:

• chr13-72761401-T-C
• rs559776849
• NM_014953.5:c.2632A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014953.5(DIS3):​c.2632A>G​(p.Lys878Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,456,522 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. K878Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: DIS3 NM_014953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.74
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.2632A>G	p.Lys878Glu	missense	Exon 19 of 21	NP_055768.3
	DIS3	NM_001128226.3		c.2542A>G	p.Lys848Glu	missense	Exon 19 of 21	NP_001121698.1	Q9Y2L1-2
	DIS3	NM_001322348.2		c.2263A>G	p.Lys755Glu	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.2632A>G	p.Lys878Glu	missense	Exon 19 of 21	ENSP00000366997.4	Q9Y2L1-1
	DIS3	ENST00000377780.8	TSL:1	c.2542A>G	p.Lys848Glu	missense	Exon 19 of 21	ENSP00000367011.4	Q9Y2L1-2
	DIS3	ENST00000545453.5	TSL:1	c.2146A>G	p.Lys716Glu	missense	Exon 20 of 23	ENSP00000440058.1	G3V1J5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1456522 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724458

African (AFR) AF: 0.00 AC: 0 AN: 33156

American (AMR) AF: 0.00 AC: 0 AN: 42920

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25980

East Asian (EAS) AF: 0.00 AC: 0 AN: 39546

South Asian (SAS) AF: 0.00 AC: 0 AN: 84902

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53258

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110826

Other (OTH) AF: 0.00 AC: 0 AN: 60182

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	23
DANN	Benign	0.81
DEOGEN2	Benign	0.010	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.93	D
M_CAP	Benign	0.0099	T
MetaRNN	Uncertain	0.43	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		7.7
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.18
Sift	Benign	0.78	T
Sift4G	Benign	1.0	T
Polyphen		0.29	B
Vest4		0.70
MutPred		0.50		Loss of methylation at K878 (P = 0.013)
MVP		0.29
MPC		0.19
ClinPred		0.64	D
GERP RS		6.0
Varity_R		0.37
gMVP		0.74
Mutation Taster		=38/62	disease causing

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

Other links and lift over

dbSNP: rs559776849; hg19: chr13-73335539;