chr1-241881973-C-G

Variant names:

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

Variant summary

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

The NM_006027.4(EXO1):​c.2167C>G​(p.Arg723Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: EXO1 NM_006027.4 missense
• Clinical Significance: Not reported in ClinVar
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006027.4. 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>G	p.Arg723Gly	missense	Exon 14 of 16	NP_569082.2
	EXO1	NM_006027.4		c.2167C>G	p.Arg723Gly	missense	Exon 12 of 14	NP_006018.4
	EXO1	NM_001319224.2		c.2164C>G	p.Arg722Gly	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>G	p.Arg723Gly	missense	Exon 14 of 16	ENSP00000355506.3
	EXO1	ENST00000348581.9	TSL:1	c.2167C>G	p.Arg723Gly	missense	Exon 12 of 14	ENSP00000311873.5
	EXO1	ENST00000518483.5	TSL:1	c.2167C>G	p.Arg723Gly	missense	Exon 12 of 14	ENSP00000430251.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 91577

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.089
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.51	T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N
PhyloP100		0.58
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.69	N
REVEL	Benign	0.032
Sift	Benign	0.28	T
Sift4G	Benign	0.43	T
Polyphen		0.012	B
Vest4		0.14
MutPred		0.18		Loss of stability (P = 0.0172)
MVP		0.22
MPC		0.059
ClinPred		0.10	T
GERP RS		1.8
Varity_R		0.069
gMVP		0.12
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.48		Position offset: 44

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

Other links and lift over

dbSNP: rs1635498; hg19: chr1-242045275;