1-241879243-A-G

Variant names:

Variant summary

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

The NM_130398.4(EXO1):c.2009A>G(p.Glu670Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.645 in 1,595,848 control chromosomes in the GnomAD database, including 333,187 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).

Frequency

Genomes: 𝑓 0.66 ( 33490 hom., cov: 33)

Exomes 𝑓: 0.64 ( 299697 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: -0.823

Publications

66 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=1.206314E-6).

BP6

Variant 1-241879243-A-G is Benign according to our data. Variant chr1-241879243-A-G is described in ClinVar as Benign. ClinVar VariationId is 3059237.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.791 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4 link	c.2009A>G	p.Glu670Gly	missense_variant	Exon 13 of 16	ENST00000366548.8	NP_569082.2	Q9UQ84-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXO1	ENST00000366548.8 link	c.2009A>G	p.Glu670Gly	missense_variant	Exon 13 of 16	1	NM_130398.4	ENSP00000355506.3	Q9UQ84-1
EXO1	ENST00000348581.9 link	c.2009A>G	p.Glu670Gly	missense_variant	Exon 11 of 14	1		ENSP00000311873.5	Q9UQ84-1
EXO1	ENST00000518483.5 link	c.2009A>G	p.Glu670Gly	missense_variant	Exon 11 of 14	1		ENSP00000430251.1	Q9UQ84-4
EXO1	ENST00000521202.2 link	c.203A>G	p.Glu68Gly	missense_variant	Exon 1 of 3	5		ENSP00000428326.1	H0YAZ2

Frequencies

GnomAD3 genomes

AF:

0.661

AC:

100430

AN:

151998

Hom.:

33459

Cov.:

show subpopulations

Gnomad AFR

AF:

0.692

Gnomad AMI

AF:

0.657

Gnomad AMR

AF:

0.705

Gnomad ASJ

AF:

0.638

Gnomad EAS

AF:

0.813

Gnomad SAS

AF:

0.597

Gnomad FIN

AF:

0.601

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.636

Gnomad OTH

AF:

0.656

GnomAD2 exomes

AF:

0.659

AC:

156451

AN:

237530

AF XY:

0.652

show subpopulations

Gnomad AFR exome

AF:

0.700

Gnomad AMR exome

AF:

0.730

Gnomad ASJ exome

AF:

0.642

Gnomad EAS exome

AF:

0.819

Gnomad FIN exome

AF:

0.599

Gnomad NFE exome

AF:

0.635

Gnomad OTH exome

AF:

0.642

GnomAD4 exome

AF:

0.643

AC:

928129

AN:

1443732

Hom.:

299697

Cov.:

AF XY:

0.641

AC XY:

459259

AN XY:

716700

show subpopulations

African (AFR)

AF:

0.693

AC:

22606

AN:

32616

American (AMR)

AF:

0.723

AC:

30275

AN:

41894

Ashkenazi Jewish (ASJ)

AF:

0.644

AC:

16119

AN:

25030

East Asian (EAS)

AF:

0.803

AC:

31738

AN:

39504

South Asian (SAS)

AF:

0.589

AC:

49049

AN:

83250

European-Finnish (FIN)

AF:

0.611

AC:

32353

AN:

52946

Middle Eastern (MID)

AF:

0.625

AC:

3532

AN:

5652

European-Non Finnish (NFE)

AF:

0.638

AC:

703909

AN:

1103326

Other (OTH)

AF:

0.648

AC:

38548

AN:

59514

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

17102

34203

51305

68406

85508

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18866

37732

56598

75464

94330

<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:

0.661

AC:

100511

AN:

152116

Hom.:

33490

Cov.:

AF XY:

0.660

AC XY:

49077

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.692

AC:

28721

AN:

41500

American (AMR)

AF:

0.705

AC:

10776

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.638

AC:

2213

AN:

3470

East Asian (EAS)

AF:

0.812

AC:

4195

AN:

5168

South Asian (SAS)

AF:

0.597

AC:

2877

AN:

4816

European-Finnish (FIN)

AF:

0.601

AC:

6352

AN:

10572

Middle Eastern (MID)

AF:

0.636

AC:

187

AN:

294

European-Non Finnish (NFE)

AF:

0.635

AC:

43204

AN:

67986

Other (OTH)

AF:

0.657

AC:

1388

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1764

3528

5293

7057

8821

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

810

1620

2430

3240

4050

<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:

0.644

Hom.:

87048

Bravo

AF:

0.674

TwinsUK

AF:

0.652

AC:

2419

ALSPAC

AF:

0.619

AC:

2385

ESP6500AA

AF:

0.700

AC:

3086

ESP6500EA

AF:

0.632

AC:

5433

ExAC

AF:

0.655

AC:

79491

Asia WGS

AF:

0.690

AC:

2402

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EXO1-related disorder

Benign:1

Oct 17, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.054

BayesDel_addAF

Benign

-0.71

BayesDel_noAF

Benign

-0.65

CADD

Benign

0.16

(source)

DANN

Benign

0.75

DEOGEN2

Benign

0.13

T;T;.

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.0

FATHMM_MKL

Benign

0.025

LIST_S2

Benign

0.080

.;T;T

MetaRNN

Benign

0.0000012

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.41

N;N;N

PhyloP100

-0.82

PrimateAI

Benign

0.21

PROVEAN

Benign

-1.6

N;N;N

REVEL

Benign

0.032

Sift

Benign

0.38

T;T;T

Sift4G

Benign

0.36

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.023

MPC

0.054

ClinPred

0.0041

GERP RS

-5.5

PromoterAI

-0.080

Neutral

(source)

Varity_R

0.030

gMVP

0.17

Mutation Taster

=99/1

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over