chr1-241852407-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_130398.4(EXO1):c.277A>G(p.Arg93Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,597,900 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 19 hom., cov: 32)

Exomes 𝑓: 0.00090 ( 23 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 1.14

Publications

7 publications found

Variant links:

COSMIC-nc: COSV105266949

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009332746).

BP6

Variant 1-241852407-A-G is Benign according to our data. Variant chr1-241852407-A-G is described in ClinVar as Benign. ClinVar VariationId is 782400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00887 (1351/152346) while in subpopulation AFR AF = 0.0314 (1307/41574). AF 95% confidence interval is 0.03. There are 19 homozygotes in GnomAd4. There are 630 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 1351 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4 link	c.277A>G	p.Arg93Gly	missense_variant	Exon 5 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.277A>G	p.Arg93Gly	missense_variant	Exon 5 of 16	1	NM_130398.4	ENSP00000355506.3		Q9UQ84-1

Frequencies

GnomAD3 genomes

AF:

0.00887

AC:

1351

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0315

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00478

GnomAD2 exomes

AF:

0.00232

AC:

580

AN:

250464

AF XY:

0.00162

show subpopulations

Gnomad AFR exome

AF:

0.0321

Gnomad AMR exome

AF:

0.00142

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000440

Gnomad OTH exome

AF:

0.000490

GnomAD4 exome

AF:

0.000897

AC:

1297

AN:

1445554

Hom.:

Cov.:

AF XY:

0.000773

AC XY:

557

AN XY:

720214

show subpopulations

African (AFR)

AF:

0.0337

AC:

1116

AN:

33098

American (AMR)

AF:

0.00152

AC:

AN:

44680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26026

East Asian (EAS)

AF:

0.00

AC:

AN:

39572

South Asian (SAS)

AF:

0.0000349

AC:

AN:

85924

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52372

Middle Eastern (MID)

AF:

0.00105

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.0000118

AC:

AN:

1098344

Other (OTH)

AF:

0.00152

AC:

AN:

59810

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

116

173

231

289

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

102

136

170

<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:

0.00887

AC:

1351

AN:

152346

Hom.:

Cov.:

AF XY:

0.00846

AC XY:

630

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.0314

AC:

1307

AN:

41574

American (AMR)

AF:

0.00196

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68032

Other (OTH)

AF:

0.00473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

130

195

260

325

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00263

Hom.:

Bravo

AF:

0.0104

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0329

AC:

145

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00277

AC:

336

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 27, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

EXO1-related disorder

Benign:1

May 20, 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

Pathogenic

0.69

BayesDel_addAF

Benign

-0.30

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

T;T;.;T

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.86

.;D;D;D

MetaRNN

Benign

0.0093

T;T;T;T

MetaSVM

Benign

-0.51

MutationAssessor

Uncertain

2.4

M;M;M;.

PhyloP100

1.1

PrimateAI

Uncertain

0.63

PROVEAN

Pathogenic

-6.1

D;D;D;D

REVEL

Benign

0.23

Sift

Uncertain

0.0030

D;D;D;D

Sift4G

Uncertain

0.0040

D;D;D;T

Polyphen

1.0

D;D;D;.

Vest4

0.74

MVP

0.78

MPC

0.36

ClinPred

0.066

GERP RS

5.0

Varity_R

0.70

gMVP

0.74

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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