rs735943

Variant names:

• chr1-241866849-A-G
• rs735943
• NM_130398.4:c.1061A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-241866849-A-G
• chr1-241866849-A-C
• chr1-241866849-A-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.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. 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 0.59 (27048 hom., cov: 32)
  • Exomes 𝑓: 0.56 (234550 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.399
• Publications: 62 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=7.037361E-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 VariationId 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.

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.1061A>G	p.His354Arg	missense	Exon 11 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.1061A>G	p.His354Arg	missense	Exon 9 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.1061A>G	p.His354Arg	missense	Exon 10 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.1061A>G	p.His354Arg	missense	Exon 11 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.1061A>G	p.His354Arg	missense	Exon 9 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.1061A>G	p.His354Arg	missense	Exon 9 of 14	ENSP00000430251.1	Q9UQ84-4

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

GnomAD2 exomes AF: 0.598 AC: 150353 AN: 251406 AF XY: 0.589

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 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

African (AFR) AF: 0.621 AC: 20736 AN: 33416

American (AMR) AF: 0.713 AC: 31893 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11480 AN: 26102

East Asian (EAS) AF: 0.787 AC: 31207 AN: 39676

South Asian (SAS) AF: 0.535 AC: 46123 AN: 86172

European-Finnish (FIN) AF: 0.606 AC: 32351 AN: 53414

Middle Eastern (MID) AF: 0.540 AC: 3111 AN: 5764

European-Non Finnish (NFE) AF: 0.552 AC: 611361 AN: 1108294

Other (OTH) AF: 0.566 AC: 34117 AN: 60248

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

African (AFR) AF: 0.617 AC: 25569 AN: 41442

American (AMR) AF: 0.673 AC: 10278 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.444 AC: 1541 AN: 3470

East Asian (EAS) AF: 0.796 AC: 4110 AN: 5166

South Asian (SAS) AF: 0.544 AC: 2624 AN: 4822

European-Finnish (FIN) AF: 0.605 AC: 6374 AN: 10540

Middle Eastern (MID) AF: 0.592 AC: 174 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37760 AN: 67976

Other (OTH) AF: 0.596 AC: 1251 AN: 2100

Alfa AF: 0.567 Hom.: 93305

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

ClinVar submissions

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	0.055
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	1.1
DANN	Benign	0.13
DEOGEN2	Benign	0.094	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.94
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.24	T
MetaRNN	Benign	7.0e-7	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.40
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.92	N
REVEL	Benign	0.042
Sift	Benign	1.0	T
Sift4G	Benign	0.67	T
Polyphen		0.0	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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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