1-241866849-A-G

Position:

• chr1-241866849-A-G

Variant summary

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

The ENST00000366548.8(EXO1):​c.1061A>G​(p.His354Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.567 in 1,609,800 control chromosomes in the GnomAD database, including 261,598 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 0.59 (27048 hom., cov: 32)
  • Exomes 𝑓: 0.56 (234550 hom.)
• Consequence: EXO1 ENST00000366548.8 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.399

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=7.037361E-7).
• BP6: Variant 1-241866849-A-G is Benign according to our data. Variant chr1-241866849-A-G is described in ClinVar as [Benign]. Clinvar id is 3060962.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.775 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXO1	NM_130398.4	c.1061A>G	p.His354Arg	missense_variant	11/16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.1061A>G	p.His354Arg	missense_variant	11/16	1	NM_130398.4	ENSP00000355506	P2
EXO1	ENST00000348581.9	c.1061A>G	p.His354Arg	missense_variant	9/14	1		ENSP00000311873	P2
EXO1	ENST00000518483.5	c.1061A>G	p.His354Arg	missense_variant	9/14	1		ENSP00000430251	A2

Frequencies

GnomAD3 genomes AF: 0.593 AC: 90060 AN: 151872 Hom.: 27013 Cov.: 32

Gnomad AFR AF: 0.617

Gnomad AMI AF: 0.520

Gnomad AMR AF: 0.672

Gnomad ASJ AF: 0.444

Gnomad EAS AF: 0.796

Gnomad SAS AF: 0.544

Gnomad FIN AF: 0.605

Gnomad MID AF: 0.579

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.593

GnomAD3 exomes AF: 0.598 AC: 150353 AN: 251406 Hom.: 46068 AF XY: 0.589 AC XY: 79978 AN XY: 135870

Gnomad AFR exome AF: 0.621

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.441

Gnomad EAS exome AF: 0.797

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.602

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.575

GnomAD4 exome AF: 0.564 AC: 822379 AN: 1457810 Hom.: 234550 Cov.: 35 AF XY: 0.563 AC XY: 408352 AN XY: 725376

Gnomad4 AFR exome AF: 0.621

Gnomad4 AMR exome AF: 0.713

Gnomad4 ASJ exome AF: 0.440

Gnomad4 EAS exome AF: 0.787

Gnomad4 SAS exome AF: 0.535

Gnomad4 FIN exome AF: 0.606

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.566

GnomAD4 genome AF: 0.593 AC: 90153 AN: 151990 Hom.: 27048 Cov.: 32 AF XY: 0.598 AC XY: 44439 AN XY: 74310

Gnomad4 AFR AF: 0.617

Gnomad4 AMR AF: 0.673

Gnomad4 ASJ AF: 0.444

Gnomad4 EAS AF: 0.796

Gnomad4 SAS AF: 0.544

Gnomad4 FIN AF: 0.605

Gnomad4 NFE AF: 0.555

Gnomad4 OTH AF: 0.596

Alfa AF: 0.561 Hom.: 59078

Bravo AF: 0.600

TwinsUK AF: 0.561 AC: 2081

ALSPAC AF: 0.545 AC: 2101

ESP6500AA AF: 0.622 AC: 2739

ESP6500EA AF: 0.540 AC: 4641

ExAC AF: 0.593 AC: 71981

Asia WGS AF: 0.673 AC: 2342 AN: 3478

EpiCase AF: 0.550

EpiControl AF: 0.545

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	0.055
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.13
DEOGEN2	Benign	0.094	T;T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	.;T;T
MetaRNN	Benign	7.0e-7	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L;L;L
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.92	N;N;N
REVEL	Benign	0.042
Sift	Benign	1.0	T;T;T
Sift4G	Benign	0.67	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.0040
MPC		0.056
ClinPred		0.0029	T
GERP RS		-0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.026
gMVP		0.43

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: rs735943; hg19: chr1-242030151; COSMIC: COSV62217725;