rs1047840

Positions:

• chr1-241878999-G-A
• chr1-241878999-G-C

Variant summary

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

The NM_130398.4(EXO1):​c.1765G>A​(p.Glu589Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.377 in 1,613,610 control chromosomes in the GnomAD database, including 116,572 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 0.40 (12502 hom., cov: 32)
  • Exomes 𝑓: 0.37 (104070 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: -0.0230

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=1.9711256E-4).
• BP6: Variant 1-241878999-G-A is Benign according to our data. Variant chr1-241878999-G-A is described in ClinVar as [Benign]. Clinvar id is 3059609.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.466 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXO1	NM_130398.4	c.1765G>A	p.Glu589Lys	missense_variant	13/16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.1765G>A	p.Glu589Lys	missense_variant	13/16	1	NM_130398.4	ENSP00000355506	P2
EXO1	ENST00000348581.9	c.1765G>A	p.Glu589Lys	missense_variant	11/14	1		ENSP00000311873	P2
EXO1	ENST00000518483.5	c.1765G>A	p.Glu589Lys	missense_variant	11/14	1		ENSP00000430251	A2
EXO1	ENST00000521202.2			upstream_gene_variant		5		ENSP00000428326

Frequencies

GnomAD3 genomes AF: 0.399 AC: 60591 AN: 151844 Hom.: 12463 Cov.: 32

Gnomad AFR AF: 0.471

Gnomad AMI AF: 0.315

Gnomad AMR AF: 0.378

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.207

Gnomad SAS AF: 0.291

Gnomad FIN AF: 0.419

Gnomad MID AF: 0.339

Gnomad NFE AF: 0.382

Gnomad OTH AF: 0.387

GnomAD3 exomes AF: 0.361 AC: 90738 AN: 251400 Hom.: 17062 AF XY: 0.356 AC XY: 48317 AN XY: 135858

Gnomad AFR exome AF: 0.477

Gnomad AMR exome AF: 0.367

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.182

Gnomad SAS exome AF: 0.291

Gnomad FIN exome AF: 0.417

Gnomad NFE exome AF: 0.377

Gnomad OTH exome AF: 0.360

GnomAD4 exome AF: 0.374 AC: 546853 AN: 1461648 Hom.: 104070 Cov.: 39 AF XY: 0.371 AC XY: 270074 AN XY: 727156

Gnomad4 AFR exome AF: 0.475

Gnomad4 AMR exome AF: 0.375

Gnomad4 ASJ exome AF: 0.397

Gnomad4 EAS exome AF: 0.193

Gnomad4 SAS exome AF: 0.295

Gnomad4 FIN exome AF: 0.414

Gnomad4 NFE exome AF: 0.382

Gnomad4 OTH exome AF: 0.374

GnomAD4 genome AF: 0.399 AC: 60687 AN: 151962 Hom.: 12502 Cov.: 32 AF XY: 0.395 AC XY: 29352 AN XY: 74282

Gnomad4 AFR AF: 0.472

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.380

Gnomad4 EAS AF: 0.208

Gnomad4 SAS AF: 0.290

Gnomad4 FIN AF: 0.419

Gnomad4 NFE AF: 0.382

Gnomad4 OTH AF: 0.383

Alfa AF: 0.375 Hom.: 27180

Bravo AF: 0.398

TwinsUK AF: 0.372 AC: 1380

ALSPAC AF: 0.392 AC: 1509

ESP6500AA AF: 0.475 AC: 2093

ESP6500EA AF: 0.375 AC: 3223

ExAC AF: 0.361 AC: 43824

Asia WGS AF: 0.316 AC: 1097 AN: 3478

EpiCase AF: 0.363

EpiControl AF: 0.371

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 18, 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	0.062
BayesDel_addAF	Benign	-0.78	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.50
DANN	Benign	0.41
DEOGEN2	Benign	0.10	T;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.0098	N
LIST_S2	Benign	0.21	.;T;T
MetaRNN	Benign	0.00020	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.60	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.18	N;N;N
REVEL	Benign	0.011
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.58	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.019
MPC		0.053
ClinPred		0.00094	T
GERP RS		-3.3
Varity_R		0.016
gMVP		0.19

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: rs1047840; hg19: chr1-242042301; COSMIC: COSV62216883; COSMIC: COSV62216883;