NM_014953.5:c.2533A>G

Variant names:

• chr13-72761500-T-C
• rs35036619
• NM_014953.5:c.2533A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014953.5(DIS3):​c.2533A>G​(p.Ile845Val) variant causes a missense change. The variant allele was found at a frequency of 0.00152 in 1,585,140 control chromosomes in the GnomAD database, including 40 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 Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.0084 (25 hom., cov: 32)
  • Exomes 𝑓: 0.00079 (15 hom.)
• Consequence: DIS3 NM_014953.5 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 4.91
• Publications: 6 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: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0048285425).
• BP6: Variant 13-72761500-T-C is Benign according to our data. Variant chr13-72761500-T-C is described in ClinVar as Benign. ClinVar VariationId is 2443114.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00837 (1275/152318) while in subpopulation AFR AF = 0.0296 (1232/41564). AF 95% confidence interval is 0.0283. There are 25 homozygotes in GnomAd4. There are 602 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 25 AR gene

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.2533A>G	p.Ile845Val	missense	Exon 19 of 21	NP_055768.3
	DIS3	NM_001128226.3		c.2443A>G	p.Ile815Val	missense	Exon 19 of 21	NP_001121698.1	Q9Y2L1-2
	DIS3	NM_001322348.2		c.2164A>G	p.Ile722Val	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.2533A>G	p.Ile845Val	missense	Exon 19 of 21	ENSP00000366997.4	Q9Y2L1-1
	DIS3	ENST00000377780.8	TSL:1	c.2443A>G	p.Ile815Val	missense	Exon 19 of 21	ENSP00000367011.4	Q9Y2L1-2
	DIS3	ENST00000545453.5	TSL:1	c.2047A>G	p.Ile683Val	missense	Exon 20 of 23	ENSP00000440058.1	G3V1J5

Frequencies

GnomAD3 genomes AF: 0.00836 AC: 1273 AN: 152200 Hom.: 25 Cov.: 32

Gnomad AFR AF: 0.0297

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00209 AC: 472 AN: 225322 AF XY: 0.00138

Gnomad AFR exome AF: 0.0284

Gnomad AMR exome AF: 0.000919

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000187

Gnomad OTH exome AF: 0.000744

GnomAD4 exome AF: 0.000795 AC: 1139 AN: 1432822 Hom.: 15 Cov.: 31 AF XY: 0.000642 AC XY: 457 AN XY: 712170

African (AFR) AF: 0.0302 AC: 955 AN: 31664

American (AMR) AF: 0.00110 AC: 40 AN: 36494

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24886

East Asian (EAS) AF: 0.00 AC: 0 AN: 39388

South Asian (SAS) AF: 0.0000501 AC: 4 AN: 79836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52826

Middle Eastern (MID) AF: 0.00106 AC: 6 AN: 5642

European-Non Finnish (NFE) AF: 0.0000209 AC: 23 AN: 1102948

Other (OTH) AF: 0.00188 AC: 111 AN: 59138

GnomAD4 genome AF: 0.00837 AC: 1275 AN: 152318 Hom.: 25 Cov.: 32 AF XY: 0.00808 AC XY: 602 AN XY: 74490

African (AFR) AF: 0.0296 AC: 1232 AN: 41564

American (AMR) AF: 0.00229 AC: 35 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2112

Alfa AF: 0.00298 Hom.: 18

Bravo AF: 0.00929

ESP6500AA AF: 0.0279 AC: 123

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00255 AC: 310

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	16
DANN	Benign	0.94
DEOGEN2	Benign	0.0039	T
Eigen	Benign	-0.095
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
MetaRNN	Benign	0.0048	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N
PhyloP100		4.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.27	N
REVEL	Benign	0.059
Sift	Benign	0.95	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.14
MVP		0.30
MPC		0.11
ClinPred		0.016	T
GERP RS		5.9
Varity_R		0.041
gMVP		0.21
Mutation Taster		=91/9	polymorphism

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: rs35036619; hg19: chr13-73335638; COSMIC: COSV66707819;