Genetic Variant EXO1:p.Pro757Leu (chr1-241885372-C-T) – ACMG Classification: Benign (-13 pts)

Variant summary

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

The NM_130398.4(EXO1):c.2270C>T(p.Pro757Leu) variant causes a missense change. The variant allele was found at a frequency of 0.176 in 1,612,938 control chromosomes in the GnomAD database, including 27,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.19 ( 3100 hom., cov: 31)

Exomes 𝑓: 0.17 ( 24712 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 6.47

Publications

67 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=0.0037188828).

BP6

Variant 1-241885372-C-T is Benign according to our data. Variant chr1-241885372-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060942.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4 link	c.2270C>T	p.Pro757Leu	missense_variant	Exon 15 of 16	ENST00000366548.8	NP_569082.2	Q9UQ84-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8 link	c.2270C>T	p.Pro757Leu	missense_variant	Exon 15 of 16	1	NM_130398.4	ENSP00000355506.3		Q9UQ84-1

Frequencies

GnomAD3 genomes

AF:

0.189

AC:

28757

AN:

151760

Hom.:

3099

Cov.:

show subpopulations

Gnomad AFR

AF:

0.182

Gnomad AMI

AF:

0.211

Gnomad AMR

AF:

0.306

Gnomad ASJ

AF:

0.108

Gnomad EAS

AF:

0.442

Gnomad SAS

AF:

0.179

Gnomad FIN

AF:

0.149

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.159

Gnomad OTH

AF:

0.198

GnomAD2 exomes

AF:

0.210

AC:

52701

AN:

250846

AF XY:

0.200

show subpopulations

Gnomad AFR exome

AF:

0.186

Gnomad AMR exome

AF:

0.387

Gnomad ASJ exome

AF:

0.114

Gnomad EAS exome

AF:

0.429

Gnomad FIN exome

AF:

0.147

Gnomad NFE exome

AF:

0.157

Gnomad OTH exome

AF:

0.198

GnomAD4 exome

AF:

0.174

AC:

254891

AN:

1461060

Hom.:

24712

Cov.:

AF XY:

0.173

AC XY:

125915

AN XY:

726874

show subpopulations

African (AFR)

AF:

0.182

AC:

6081

AN:

33462

American (AMR)

AF:

0.376

AC:

16773

AN:

44666

Ashkenazi Jewish (ASJ)

AF:

0.115

AC:

3006

AN:

26128

East Asian (EAS)

AF:

0.416

AC:

16500

AN:

39674

South Asian (SAS)

AF:

0.170

AC:

14666

AN:

86242

European-Finnish (FIN)

AF:

0.154

AC:

8212

AN:

53392

Middle Eastern (MID)

AF:

0.166

AC:

953

AN:

5756

European-Non Finnish (NFE)

AF:

0.160

AC:

177950

AN:

1111386

Other (OTH)

AF:

0.178

AC:

10750

AN:

60354

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

9775

19551

29326

39102

48877

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

6564

13128

19692

26256

32820

<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:

0.190

AC:

28794

AN:

151878

Hom.:

3100

Cov.:

AF XY:

0.193

AC XY:

14339

AN XY:

74190

show subpopulations

African (AFR)

AF:

0.182

AC:

7557

AN:

41418

American (AMR)

AF:

0.307

AC:

4684

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.108

AC:

374

AN:

3470

East Asian (EAS)

AF:

0.441

AC:

2270

AN:

5150

South Asian (SAS)

AF:

0.179

AC:

860

AN:

4812

European-Finnish (FIN)

AF:

0.149

AC:

1570

AN:

10528

Middle Eastern (MID)

AF:

0.143

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.159

AC:

10831

AN:

67934

Other (OTH)

AF:

0.197

AC:

414

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1140

2280

3419

4559

5699

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

302

604

906

1208

1510

<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:

0.173

Hom.:

11069

Bravo

AF:

0.206

TwinsUK

AF:

0.163

AC:

604

ALSPAC

AF:

0.153

AC:

589

ESP6500AA

AF:

0.184

AC:

810

ESP6500EA

AF:

0.159

AC:

1367

ExAC

AF:

0.203

AC:

24657

Asia WGS

AF:

0.311

AC:

1083

AN:

3478

EpiCase

AF:

0.152

EpiControl

AF:

0.152

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

EXO1-related disorder

Benign:1

Oct 18, 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

0.079

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.52

D;D;.

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.76

.;T;T

MetaRNN

Benign

0.0037

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Uncertain

2.4

M;M;M

PhyloP100

6.5

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-4.2

D;D;D

REVEL

Benign

0.20

Sift

Uncertain

0.021

D;D;D

Sift4G

Uncertain

0.040

D;D;D

Polyphen

0.58

P;P;P

Vest4

0.13

MPC

0.19

ClinPred

0.047

GERP RS

6.0

Varity_R

0.12

gMVP

0.18

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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