rs4150001

chr1-241885378-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.326

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]

ACMG classification

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 GnomAd at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.2276G>A	p.Gly759Glu	missense_variant	15/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.2276G>A	p.Gly759Glu	missense_variant	15/16	1	NM_130398.4	P2

Frequencies

GnomAD3 genomes AF: 0.00813 AC: 1236 AN: 151942 Hom.: 12 Cov.: 32

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.: 23 AF XY: 0.00842 AC XY: 1143 AN XY: 135780

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.: 78 Cov.: 32 AF XY: 0.00881 AC XY: 6405 AN XY: 727154

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.: 12 Cov.: 32 AF XY: 0.00861 AC XY: 640 AN XY: 74336

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.: 8

Bravo AF: 0.00585

TwinsUK AF: 0.00836 AC: 31

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00907 AC: 78

ExAC AF: 0.00844 AC: 1025

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00791

EpiControl AF: 0.00931

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Sep 13, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	EXO1: BP4, BS2 -

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, criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.40
Cadd	Benign	12
Dann	Benign	0.97
DEOGEN2	Benign	0.19	T;T;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.61
FATHMM_MKL	Benign	0.18	N
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.31	T
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	T
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

Other links and lift over

dbSNP: rs4150001; hg19: chr1-242048680; COSMIC: COSV99049561;