1-241881973-C-T

Position:

• chr1-241881973-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_130398.4(EXO1):​c.2167C>T​(p.Arg723Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,582,088 control chromosomes in the GnomAD database, including 739,663 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.95 (68223 hom., cov: 31)
  • Exomes 𝑓: 0.97 (671440 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.577

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.155276E-7).
• BP6: Variant 1-241881973-C-T is Benign according to our data. Variant chr1-241881973-C-T is described in ClinVar as [Benign]. Clinvar id is 3060120.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.2167C>T	p.Arg723Cys	missense_variant	14/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.2167C>T	p.Arg723Cys	missense_variant	14/16	1	NM_130398.4	P2
EXO1	ENST00000348581.9	c.2167C>T	p.Arg723Cys	missense_variant	12/14	1		P2
EXO1	ENST00000518483.5	c.2167C>T	p.Arg723Cys	missense_variant	12/14	1		A2
EXO1	ENST00000521202.2	c.304+2630C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.946 AC: 143815 AN: 152038 Hom.: 68186 Cov.: 31

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.928

Gnomad AMR AF: 0.973

Gnomad ASJ AF: 0.943

Gnomad EAS AF: 0.871

Gnomad SAS AF: 0.937

Gnomad FIN AF: 0.994

Gnomad MID AF: 0.930

Gnomad NFE AF: 0.976

Gnomad OTH AF: 0.943

GnomAD3 exomes AF: 0.958 AC: 239954 AN: 250514 Hom.: 115087 AF XY: 0.958 AC XY: 129766 AN XY: 135418

Gnomad AFR exome AF: 0.883

Gnomad AMR exome AF: 0.974

Gnomad ASJ exome AF: 0.936

Gnomad EAS exome AF: 0.872

Gnomad SAS exome AF: 0.945

Gnomad FIN exome AF: 0.992

Gnomad NFE exome AF: 0.976

Gnomad OTH exome AF: 0.967

GnomAD4 exome AF: 0.969 AC: 1385155 AN: 1429932 Hom.: 671440 Cov.: 26 AF XY: 0.968 AC XY: 690337 AN XY: 713000

Gnomad4 AFR exome AF: 0.881

Gnomad4 AMR exome AF: 0.974

Gnomad4 ASJ exome AF: 0.934

Gnomad4 EAS exome AF: 0.870

Gnomad4 SAS exome AF: 0.946

Gnomad4 FIN exome AF: 0.991

Gnomad4 NFE exome AF: 0.977

Gnomad4 OTH exome AF: 0.960

GnomAD4 genome AF: 0.946 AC: 143907 AN: 152156 Hom.: 68223 Cov.: 31 AF XY: 0.945 AC XY: 70285 AN XY: 74382

Gnomad4 AFR AF: 0.884

Gnomad4 AMR AF: 0.973

Gnomad4 ASJ AF: 0.943

Gnomad4 EAS AF: 0.871

Gnomad4 SAS AF: 0.938

Gnomad4 FIN AF: 0.994

Gnomad4 NFE AF: 0.976

Gnomad4 OTH AF: 0.944

Alfa AF: 0.966 Hom.: 79620

Bravo AF: 0.940

TwinsUK AF: 0.982 AC: 3640

ALSPAC AF: 0.976 AC: 3761

ESP6500AA AF: 0.886 AC: 3900

ESP6500EA AF: 0.976 AC: 8380

ExAC AF: 0.956 AC: 116091

Asia WGS AF: 0.918 AC: 3177 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EXO1-related disorder Benign:1

Benign, criteria provided, single submitter

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	0.066
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.18	T;T;.
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.48	.;T;T
MetaRNN	Benign	7.2e-7	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N;N;N
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.19	T;T;T
Sift4G	Uncertain	0.057	T;T;T
Polyphen		0.77	P;P;P
Vest4		0.061
MPC		0.12
ClinPred		0.0044	T
GERP RS		1.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.068
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.19		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: rs1635498; hg19: chr1-242045275;