Genetic Variant EXO1:p.Arg723Ser (chr1-241881973-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_130398.4(EXO1):c.2167C>A(p.Arg723Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,430,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R723C) has been classified as Benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

EXO1
NM_130398.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.577

Publications

41 publications found

Variant links:

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]

EXO1 Gene-Disease associations (from GenCC):

Lynch syndrome
Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

EXO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4 link	c.2167C>A	p.Arg723Ser	missense_variant	Exon 14 of 16	ENST00000366548.8	NP_569082.2	Q9UQ84-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
EXO1	ENST00000366548.8 link	c.2167C>A	p.Arg723Ser	missense_variant	Exon 14 of 16	1	NM_130398.4	ENSP00000355506.3	Q9UQ84-1
EXO1	ENST00000348581.9 link	c.2167C>A	p.Arg723Ser	missense_variant	Exon 12 of 14	1		ENSP00000311873.5	Q9UQ84-1
EXO1	ENST00000518483.5 link	c.2167C>A	p.Arg723Ser	missense_variant	Exon 12 of 14	1		ENSP00000430251.1	Q9UQ84-4
EXO1	ENST00000521202.2 link	c.303+2630C>A		intron_variant	Intron 1 of 2	5		ENSP00000428326.1	H0YAZ2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.99e-7

AC:

AN:

1430474

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

713256

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32910

American (AMR)

AF:

0.00

AC:

AN:

44606

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25848

East Asian (EAS)

AF:

0.00

AC:

AN:

39364

South Asian (SAS)

AF:

0.00

AC:

AN:

84360

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53218

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5706

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1085194

Other (OTH)

AF:

0.00

AC:

AN:

59268

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

91577

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.59

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.095

T;T;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.97

FATHMM_MKL

Benign

0.092

LIST_S2

Benign

0.50

.;T;T

M_CAP

Benign

0.0055

MetaRNN

Benign

0.044

T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.34

N;N;N

PhyloP100

0.58

PrimateAI

Benign

0.21

PROVEAN

Benign

0.57

N;N;N

REVEL

Benign

0.049

Sift

Benign

0.51

T;T;T

Sift4G

Benign

0.79

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.12

MutPred

0.16

Gain of phosphorylation at R723 (P = 0.0225);Gain of phosphorylation at R723 (P = 0.0225);Gain of phosphorylation at R723 (P = 0.0225);

MVP

0.21

MPC

0.053

ClinPred

0.11

GERP RS

1.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.082

gMVP

0.12

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.29

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.29

Position offset: 44

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over