Genetic Variant DIS3:p.Tyr851Phe (chr13-72761481-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_014953.5(DIS3):c.2552A>T(p.Tyr851Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000000687 in 1,455,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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 variant affecting the same amino acid position, but resulting in a different missense (i.e. Y851C) 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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.05

Publications

0 publications found

Variant links:

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]

DIS3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.19641483).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3	NM_014953.5	MANE Select	c.2552A>T	p.Tyr851Phe	missense	Exon 19 of 21	NP_055768.3
DIS3	NM_001128226.3		c.2462A>T	p.Tyr821Phe	missense	Exon 19 of 21	NP_001121698.1	Q9Y2L1-2
DIS3	NM_001322348.2		c.2183A>T	p.Tyr728Phe	missense	Exon 18 of 20	NP_001309277.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
DIS3	ENST00000377767.9	TSL:1 MANE Select	c.2552A>T	p.Tyr851Phe	missense	Exon 19 of 21	ENSP00000366997.4	Q9Y2L1-1
DIS3	ENST00000377780.8	TSL:1	c.2462A>T	p.Tyr821Phe	missense	Exon 19 of 21	ENSP00000367011.4	Q9Y2L1-2
DIS3	ENST00000545453.5	TSL:1	c.2066A>T	p.Tyr689Phe	missense	Exon 20 of 23	ENSP00000440058.1	G3V1J5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.87e-7

AC:

AN:

1455998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

724290

show subpopulations

African (AFR)

AF:

0.0000302

AC:

AN:

33152

American (AMR)

AF:

0.00

AC:

AN:

43498

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25996

East Asian (EAS)

AF:

0.00

AC:

AN:

39560

South Asian (SAS)

AF:

0.00

AC:

AN:

85074

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53208

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109580

Other (OTH)

AF:

0.00

AC:

AN:

60176

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.13

Eigen

Benign

-0.044

Eigen_PC

Benign

0.18

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.96

M_CAP

Benign

0.0015

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.24

PhyloP100

5.1

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-2.9

REVEL

Benign

0.042

Sift

Benign

0.44

Sift4G

Benign

0.39

Polyphen

0.050

Vest4

0.33

MutPred

0.39

Gain of catalytic residue at V846 (P = 9e-04)

MVP

0.35

MPC

0.13

ClinPred

0.58

GERP RS

5.9

Varity_R

0.26

gMVP

0.31

Mutation Taster

=57/43

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over