rs4150001

Positions:

chr1-241885378-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_130398.4(EXO1):c.2276G>A(p.Gly759Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00869 in 1,613,746 control chromosomes in the GnomAD database, including 90 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.0081 ( 12 hom., cov: 32)

Exomes 𝑓: 0.0088 ( 78 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.326

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 links:

EXO1 (HGNC:):

EXO1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0052691996).

BP6

Variant 1-241885378-G-A is Benign according to our data. Variant chr1-241885378-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 435103.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-241885378-G-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXO1	NM_130398.4 linkuse as main transcript	c.2276G>A	p.Gly759Glu	missense_variant	15/16	ENST00000366548.8	NP_569082.2	Q9UQ84-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8 linkuse as main transcript	c.2276G>A	p.Gly759Glu	missense_variant	15/16	1	NM_130398.4	ENSP00000355506.3		Q9UQ84-1

Frequencies

GnomAD3 genomes

AF:

0.00813

AC:

1236

AN:

151942

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00662

Gnomad ASJ

AF:

0.00288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00207

Gnomad FIN

AF:

0.0350

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00974

Gnomad OTH

AF:

0.00528

GnomAD3 exomes

AF:

0.00860

AC:

2161

AN:

251200

Hom.:

AF XY:

0.00842

AC XY:

1143

AN XY:

135780

show subpopulations

Gnomad AFR exome

AF:

0.00166

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00147

Gnomad FIN exome

AF:

0.0335

Gnomad NFE exome

AF:

0.00932

Gnomad OTH exome

AF:

0.0113

GnomAD4 exome

AF:

0.00875

AC:

12791

AN:

1461686

Hom.:

Cov.:

AF XY:

0.00881

AC XY:

6405

AN XY:

727154

show subpopulations

Gnomad4 AFR exome

AF:

0.00134

Gnomad4 AMR exome

AF:

0.00655

Gnomad4 ASJ exome

AF:

0.00119

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00141

Gnomad4 FIN exome

AF:

0.0325

Gnomad4 NFE exome

AF:

0.00905

Gnomad4 OTH exome

AF:

0.00815

GnomAD4 genome

AF:

0.00813

AC:

1237

AN:

152060

Hom.:

Cov.:

AF XY:

0.00861

AC XY:

640

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.00176

Gnomad4 AMR

AF:

0.00661

Gnomad4 ASJ

AF:

0.00288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00208

Gnomad4 FIN

AF:

0.0350

Gnomad4 NFE

AF:

0.00975

Gnomad4 OTH

AF:

0.00522

Alfa

AF:

0.00782

Hom.:

Bravo

AF:

0.00585

TwinsUK

AF:

0.00836

AC:

ALSPAC

AF:

0.00908

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00907

AC:

ExAC

AF:

0.00844

AC:

1025

Asia WGS

AF:

0.00173

AC:

AN:

3478

EpiCase

AF:

0.00791

EpiControl

AF:

0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EXO1: BP4, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 13, 2018	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 16, 2016

- -

EXO1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 09, 2019

This variant is classified as likely 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

0.15

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.40

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.19

T;T;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.75

.;T;T

MetaRNN

Benign

0.0053

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.81

L;L;L

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.7

N;N;N

REVEL

Benign

0.059

Sift

Benign

0.045

D;D;D

Sift4G

Benign

0.24

T;T;T

Polyphen

0.54

P;P;P

Vest4

0.69

MVP

0.67

MPC

0.14

ClinPred

0.0012

GERP RS

2.2

Varity_R

0.043

gMVP

0.24

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over