rs1047840

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_130398.4(EXO1):c.1765G>A(p.Glu589Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,613,610 control chromosomes in the GnomAD database, including 116,572 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E589Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.40 ( 12502 hom., cov: 32)

Exomes 𝑓: 0.37 ( 104070 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.0230

Publications

98 publications found

Variant links:

Genes affected

EXO1 (HGNC:3511): (exonuclease 1) This gene encodes a protein with 5' to 3' exonuclease activity as well as an RNase H activity. It is similar to the Saccharomyces cerevisiae protein Exo1 which interacts with Msh2 and which is involved in mismatch repair and recombination. Alternative splicing of this gene results in three transcript variants encoding two different isoforms. [provided by RefSeq, Jul 2008]

EXO1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EXO1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.9711256E-4).

BP6

Variant 1-241878999-G-A is Benign according to our data. Variant chr1-241878999-G-A is described in ClinVar as Benign. ClinVar VariationId is 3059609.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130398.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXO1	NM_130398.4	MANE Select	c.1765G>A	p.Glu589Lys	missense	Exon 13 of 16	NP_569082.2	Q9UQ84-1
EXO1	NM_006027.4		c.1765G>A	p.Glu589Lys	missense	Exon 11 of 14	NP_006018.4	Q9UQ84-1
EXO1	NM_001319224.2		c.1762G>A	p.Glu588Lys	missense	Exon 12 of 15	NP_001306153.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
EXO1	ENST00000366548.8	TSL:1 MANE Select	c.1765G>A	p.Glu589Lys	missense	Exon 13 of 16	ENSP00000355506.3	Q9UQ84-1
EXO1	ENST00000348581.9	TSL:1	c.1765G>A	p.Glu589Lys	missense	Exon 11 of 14	ENSP00000311873.5	Q9UQ84-1
EXO1	ENST00000518483.5	TSL:1	c.1765G>A	p.Glu589Lys	missense	Exon 11 of 14	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes

AF:

0.399

AC:

60591

AN:

151844

Hom.:

12463

Cov.:

show subpopulations

Gnomad AFR

AF:

0.471

Gnomad AMI

AF:

0.315

Gnomad AMR

AF:

0.378

Gnomad ASJ

AF:

0.380

Gnomad EAS

AF:

0.207

Gnomad SAS

AF:

0.291

Gnomad FIN

AF:

0.419

Gnomad MID

AF:

0.339

Gnomad NFE

AF:

0.382

Gnomad OTH

AF:

0.387

GnomAD2 exomes

AF:

0.361

AC:

90738

AN:

251400

AF XY:

0.356

show subpopulations

Gnomad AFR exome

AF:

0.477

Gnomad AMR exome

AF:

0.367

Gnomad ASJ exome

AF:

0.395

Gnomad EAS exome

AF:

0.182

Gnomad FIN exome

AF:

0.417

Gnomad NFE exome

AF:

0.377

Gnomad OTH exome

AF:

0.360

GnomAD4 exome

AF:

0.374

AC:

546853

AN:

1461648

Hom.:

104070

Cov.:

AF XY:

0.371

AC XY:

270074

AN XY:

727156

show subpopulations

African (AFR)

AF:

0.475

AC:

15916

AN:

33476

American (AMR)

AF:

0.375

AC:

16751

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.397

AC:

10381

AN:

26134

East Asian (EAS)

AF:

0.193

AC:

7673

AN:

39698

South Asian (SAS)

AF:

0.295

AC:

25436

AN:

86252

European-Finnish (FIN)

AF:

0.414

AC:

22104

AN:

53420

Middle Eastern (MID)

AF:

0.318

AC:

1834

AN:

5768

European-Non Finnish (NFE)

AF:

0.382

AC:

424168

AN:

1111790

Other (OTH)

AF:

0.374

AC:

22590

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

19796

39592

59387

79183

98979

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

13322

26644

39966

53288

66610

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.399

AC:

60687

AN:

151962

Hom.:

12502

Cov.:

AF XY:

0.395

AC XY:

29352

AN XY:

74282

show subpopulations

African (AFR)

AF:

0.472

AC:

19541

AN:

41432

American (AMR)

AF:

0.379

AC:

5777

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.380

AC:

1319

AN:

3468

East Asian (EAS)

AF:

0.208

AC:

1072

AN:

5164

South Asian (SAS)

AF:

0.290

AC:

1399

AN:

4820

European-Finnish (FIN)

AF:

0.419

AC:

4421

AN:

10560

Middle Eastern (MID)

AF:

0.330

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.382

AC:

25967

AN:

67952

Other (OTH)

AF:

0.383

AC:

807

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1859

3718

5577

7436

9295

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

566

1132

1698

2264

2830

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.381

Hom.:

54707

Bravo

AF:

0.398

TwinsUK

AF:

0.372

AC:

1380

ALSPAC

AF:

0.392

AC:

1509

ESP6500AA

AF:

0.475

AC:

2093

ESP6500EA

AF:

0.375

AC:

3223

ExAC

AF:

0.361

AC:

43824

Asia WGS

AF:

0.316

AC:

1097

AN:

3478

EpiCase

AF:

0.363

EpiControl

AF:

0.371

ClinVar

ClinVar submissions

Significance:Benign

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

EXO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.062

BayesDel_addAF

Benign

-0.78

BayesDel_noAF

Benign

-0.75

CADD

Benign

0.50

(source)

DANN

Benign

0.41

DEOGEN2

Benign

0.10

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.0098

LIST_S2

Benign

0.21

MetaRNN

Benign

0.00020

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-0.60

PhyloP100

-0.023

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.18

REVEL

Benign

0.011

Sift

Benign

1.0

Sift4G

Benign

0.58

Polyphen

0.0

Vest4

0.019

MPC

0.053

ClinPred

0.00094

GERP RS

-3.3

PromoterAI

0.00050

Neutral

(source)

Varity_R

0.016

gMVP

0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over