rs1776148

Positions:

• chr1-241879243-A-G
• chr1-241879243-A-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

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. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.66 (33490 hom., cov: 33)
  • Exomes 𝑓: 0.64 (299697 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.823

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 -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 id 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/exons	MANE	UniProt
EXO1	NM_130398.4	c.2009A>G	p.Glu670Gly	missense_variant	13/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.2009A>G	p.Glu670Gly	missense_variant	13/16	1	NM_130398.4	P2
EXO1	ENST00000348581.9	c.2009A>G	p.Glu670Gly	missense_variant	11/14	1		P2
EXO1	ENST00000518483.5	c.2009A>G	p.Glu670Gly	missense_variant	11/14	1		A2
EXO1	ENST00000521202.2	c.206A>G	p.Glu69Gly	missense_variant	1/3	5

Frequencies

GnomAD3 genomes AF: 0.661 AC: 100430 AN: 151998 Hom.: 33459 Cov.: 33

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

GnomAD3 exomes AF: 0.659 AC: 156451 AN: 237530 Hom.: 52043 AF XY: 0.652 AC XY: 83577 AN XY: 128256

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 SAS exome AF: 0.592

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.: 37 AF XY: 0.641 AC XY: 459259 AN XY: 716700

Gnomad4 AFR exome AF: 0.693

Gnomad4 AMR exome AF: 0.723

Gnomad4 ASJ exome AF: 0.644

Gnomad4 EAS exome AF: 0.803

Gnomad4 SAS exome AF: 0.589

Gnomad4 FIN exome AF: 0.611

Gnomad4 NFE exome AF: 0.638

Gnomad4 OTH exome AF: 0.648

GnomAD4 genome AF: 0.661 AC: 100511 AN: 152116 Hom.: 33490 Cov.: 33 AF XY: 0.660 AC XY: 49077 AN XY: 74346

Gnomad4 AFR AF: 0.692

Gnomad4 AMR AF: 0.705

Gnomad4 ASJ AF: 0.638

Gnomad4 EAS AF: 0.812

Gnomad4 SAS AF: 0.597

Gnomad4 FIN AF: 0.601

Gnomad4 NFE AF: 0.635

Gnomad4 OTH AF: 0.657

Alfa AF: 0.642 Hom.: 59135

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

Submissions by phenotype

EXO1-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 17, 2019

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	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.16
DANN	Benign	0.75
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.080	.;T;T
MetaRNN	Benign	0.0000012	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
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	T
GERP RS		-5.5
Varity_R		0.030
gMVP		0.17

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: rs1776148; hg19: chr1-242042545; COSMIC: COSV62218364;