13-72775221-G-C

Position:

• chr13-72775221-G-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_014953.5(DIS3):​c.977C>G​(p.Thr326Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.405 in 1,611,058 control chromosomes in the GnomAD database, including 137,585 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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 nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.47 (18341 hom., cov: 32)
  • Exomes 𝑓: 0.40 (119244 hom.)
• Consequence: DIS3 NM_014953.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.363

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=2.2935894E-6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIS3	NM_014953.5	c.977C>G	p.Thr326Arg	missense_variant	6/21	ENST00000377767.9	NP_055768.3
DIS3	NM_001128226.3	c.887C>G	p.Thr296Arg	missense_variant	6/21		NP_001121698.1
DIS3	NM_001322348.2	c.608C>G	p.Thr203Arg	missense_variant	5/20		NP_001309277.1
DIS3	NM_001322349.2	c.491C>G	p.Thr164Arg	missense_variant	7/22		NP_001309278.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIS3	ENST00000377767.9	c.977C>G	p.Thr326Arg	missense_variant	6/21	1	NM_014953.5	ENSP00000366997.4
DIS3	ENST00000377780.8	c.887C>G	p.Thr296Arg	missense_variant	6/21	1		ENSP00000367011.4
DIS3	ENST00000545453.5	c.491C>G	p.Thr164Arg	missense_variant	7/23	1		ENSP00000440058.1
DIS3	ENST00000490646.1	n.977C>G		non_coding_transcript_exon_variant	6/20	5		ENSP00000436350.1

Frequencies

GnomAD3 genomes AF: 0.470 AC: 71354 AN: 151898 Hom.: 18310 Cov.: 32

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.363

Gnomad AMR AF: 0.358

Gnomad ASJ AF: 0.510

Gnomad EAS AF: 0.267

Gnomad SAS AF: 0.339

Gnomad FIN AF: 0.382

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.405

Gnomad OTH AF: 0.441

GnomAD3 exomes AF: 0.387 AC: 96347 AN: 248880 Hom.: 20368 AF XY: 0.387 AC XY: 52045 AN XY: 134554

Gnomad AFR exome AF: 0.690

Gnomad AMR exome AF: 0.240

Gnomad ASJ exome AF: 0.493

Gnomad EAS exome AF: 0.263

Gnomad SAS exome AF: 0.363

Gnomad FIN exome AF: 0.372

Gnomad NFE exome AF: 0.409

Gnomad OTH exome AF: 0.387

GnomAD4 exome AF: 0.398 AC: 581196 AN: 1459042 Hom.: 119244 Cov.: 39 AF XY: 0.397 AC XY: 288400 AN XY: 725744

Gnomad4 AFR exome AF: 0.689

Gnomad4 AMR exome AF: 0.251

Gnomad4 ASJ exome AF: 0.498

Gnomad4 EAS exome AF: 0.257

Gnomad4 SAS exome AF: 0.364

Gnomad4 FIN exome AF: 0.374

Gnomad4 NFE exome AF: 0.400

Gnomad4 OTH exome AF: 0.418

GnomAD4 genome AF: 0.470 AC: 71420 AN: 152016 Hom.: 18341 Cov.: 32 AF XY: 0.463 AC XY: 34378 AN XY: 74288

Gnomad4 AFR AF: 0.681

Gnomad4 AMR AF: 0.357

Gnomad4 ASJ AF: 0.510

Gnomad4 EAS AF: 0.267

Gnomad4 SAS AF: 0.339

Gnomad4 FIN AF: 0.382

Gnomad4 NFE AF: 0.405

Gnomad4 OTH AF: 0.437

Alfa AF: 0.420 Hom.: 10434

Bravo AF: 0.477

TwinsUK AF: 0.426 AC: 1580

ALSPAC AF: 0.392 AC: 1509

ESP6500AA AF: 0.677 AC: 2984

ESP6500EA AF: 0.415 AC: 3570

ExAC AF: 0.400 AC: 48573

EpiCase AF: 0.420

EpiControl AF: 0.420

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.056
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	11
DANN	Benign	0.72
DEOGEN2	Benign	0.010	T;.;T
Eigen	Benign	-1.1
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.050	T;T;T
MetaRNN	Benign	0.0000023	T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.45	N;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.15	N;N;N
REVEL	Benign	0.042
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.55	T;T;T
Polyphen		0.0	B;B;.
Vest4		0.067
MPC		0.15
ClinPred		0.0012	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.32

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

LitVar

Other links and lift over

dbSNP: rs7332388; hg19: chr13-73349359; COSMIC: COSV66705559;