NM_130398.4:c.2167C>T

Variant names:

• chr1-241881973-C-T
• rs1635498
• NM_130398.4:c.2167C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.95 (68223 hom., cov: 31)
  • Exomes 𝑓: 0.97 (671440 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.577
• Publications: 41 publications found

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

ACMG classification

Our verdict: Benign. The variant received -13 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 VariationId is 3060120.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.97 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130398.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	NM_130398.4	MANE Select	c.2167C>T	p.Arg723Cys	missense	Exon 14 of 16	NP_569082.2
	EXO1	NM_006027.4		c.2167C>T	p.Arg723Cys	missense	Exon 12 of 14	NP_006018.4
	EXO1	NM_001319224.2		c.2164C>T	p.Arg722Cys	missense	Exon 13 of 15	NP_001306153.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	ENST00000366548.8	TSL:1 MANE Select	c.2167C>T	p.Arg723Cys	missense	Exon 14 of 16	ENSP00000355506.3
	EXO1	ENST00000348581.9	TSL:1	c.2167C>T	p.Arg723Cys	missense	Exon 12 of 14	ENSP00000311873.5
	EXO1	ENST00000518483.5	TSL:1	c.2167C>T	p.Arg723Cys	missense	Exon 12 of 14	ENSP00000430251.1

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

GnomAD2 exomes AF: 0.958 AC: 239954 AN: 250514 AF XY: 0.958

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 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

African (AFR) AF: 0.881 AC: 28920 AN: 32834

American (AMR) AF: 0.974 AC: 43424 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24141 AN: 25840

East Asian (EAS) AF: 0.870 AC: 34237 AN: 39350

South Asian (SAS) AF: 0.946 AC: 79767 AN: 84320

European-Finnish (FIN) AF: 0.991 AC: 52753 AN: 53216

Middle Eastern (MID) AF: 0.928 AC: 5292 AN: 5704

European-Non Finnish (NFE) AF: 0.977 AC: 1059731 AN: 1084822

Other (OTH) AF: 0.960 AC: 56890 AN: 59244

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

African (AFR) AF: 0.884 AC: 36716 AN: 41518

American (AMR) AF: 0.973 AC: 14867 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.943 AC: 3271 AN: 3470

East Asian (EAS) AF: 0.871 AC: 4496 AN: 5162

South Asian (SAS) AF: 0.938 AC: 4524 AN: 4824

European-Finnish (FIN) AF: 0.994 AC: 10526 AN: 10588

Middle Eastern (MID) AF: 0.932 AC: 274 AN: 294

European-Non Finnish (NFE) AF: 0.976 AC: 66395 AN: 67998

Other (OTH) AF: 0.944 AC: 1992 AN: 2110

Alfa AF: 0.964 Hom.: 91577

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

ClinVar submissions as Germline

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	EXO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.054	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	7.2e-7	T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.036
Sift	Benign	0.19	T
Sift4G	Uncertain	0.057	T
Polyphen		0.77	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1635498; hg19: chr1-242045275; COSMIC: COSV107434510; COSMIC: COSV107434510;