rs9350

Variant names:

• chr1-241885372-C-T
• rs9350
• NM_130398.4:c.2270C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-241885372-C-T
• chr1-241885372-C-G

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.2270C>T​(p.Pro757Leu) variant causes a missense change. The variant allele was found at a frequency of 0.176 in 1,612,938 control chromosomes in the GnomAD database, including 27,812 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.19 (3100 hom., cov: 31)
  • Exomes 𝑓: 0.17 (24712 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 6.47
• Publications: 67 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=0.0037188828).
• BP6: Variant 1-241885372-C-T is Benign according to our data. Variant chr1-241885372-C-T is described in ClinVar as Benign. ClinVar VariationId is 3060942.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.426 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.2270C>T	p.Pro757Leu	missense	Exon 15 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.2270C>T	p.Pro757Leu	missense	Exon 13 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.2267C>T	p.Pro756Leu	missense	Exon 14 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.2270C>T	p.Pro757Leu	missense	Exon 15 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.2270C>T	p.Pro757Leu	missense	Exon 13 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.2270C>T	p.Pro757Leu	missense	Exon 13 of 14	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes AF: 0.189 AC: 28757 AN: 151760 Hom.: 3099 Cov.: 31

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.211

Gnomad AMR AF: 0.306

Gnomad ASJ AF: 0.108

Gnomad EAS AF: 0.442

Gnomad SAS AF: 0.179

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.159

Gnomad OTH AF: 0.198

GnomAD2 exomes AF: 0.210 AC: 52701 AN: 250846 AF XY: 0.200

Gnomad AFR exome AF: 0.186

Gnomad AMR exome AF: 0.387

Gnomad ASJ exome AF: 0.114

Gnomad EAS exome AF: 0.429

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.157

Gnomad OTH exome AF: 0.198

GnomAD4 exome AF: 0.174 AC: 254891 AN: 1461060 Hom.: 24712 Cov.: 32 AF XY: 0.173 AC XY: 125915 AN XY: 726874

African (AFR) AF: 0.182 AC: 6081 AN: 33462

American (AMR) AF: 0.376 AC: 16773 AN: 44666

Ashkenazi Jewish (ASJ) AF: 0.115 AC: 3006 AN: 26128

East Asian (EAS) AF: 0.416 AC: 16500 AN: 39674

South Asian (SAS) AF: 0.170 AC: 14666 AN: 86242

European-Finnish (FIN) AF: 0.154 AC: 8212 AN: 53392

Middle Eastern (MID) AF: 0.166 AC: 953 AN: 5756

European-Non Finnish (NFE) AF: 0.160 AC: 177950 AN: 1111386

Other (OTH) AF: 0.178 AC: 10750 AN: 60354

GnomAD4 genome AF: 0.190 AC: 28794 AN: 151878 Hom.: 3100 Cov.: 31 AF XY: 0.193 AC XY: 14339 AN XY: 74190

African (AFR) AF: 0.182 AC: 7557 AN: 41418

American (AMR) AF: 0.307 AC: 4684 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 374 AN: 3470

East Asian (EAS) AF: 0.441 AC: 2270 AN: 5150

South Asian (SAS) AF: 0.179 AC: 860 AN: 4812

European-Finnish (FIN) AF: 0.149 AC: 1570 AN: 10528

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.159 AC: 10831 AN: 67934

Other (OTH) AF: 0.197 AC: 414 AN: 2100

Alfa AF: 0.173 Hom.: 11069

Bravo AF: 0.206

TwinsUK AF: 0.163 AC: 604

ALSPAC AF: 0.153 AC: 589

ESP6500AA AF: 0.184 AC: 810

ESP6500EA AF: 0.159 AC: 1367

ExAC AF: 0.203 AC: 24657

Asia WGS AF: 0.311 AC: 1083 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.152

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	0.079
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0037	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		6.5
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-4.2	D
REVEL	Benign	0.20
Sift	Uncertain	0.021	D
Sift4G	Uncertain	0.040	D
Polyphen		0.58	P
Vest4		0.13
MPC		0.19
ClinPred		0.047	T
GERP RS		6.0
Varity_R		0.12
gMVP		0.18
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs9350; hg19: chr1-242048674; COSMIC: COSV62217578;