1-241881973-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_130398.4(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_130398.4 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
EXO1	NM_130398.4	c.2167C>G	p.Arg723Gly	missense_variant	Exon 14 of 16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.2167C>G	p.Arg723Gly	missense_variant	Exon 14 of 16	1	NM_130398.4	ENSP00000355506.3
EXO1	ENST00000348581.9	c.2167C>G	p.Arg723Gly	missense_variant	Exon 12 of 14	1		ENSP00000311873.5
EXO1	ENST00000518483.5	c.2167C>G	p.Arg723Gly	missense_variant	Exon 12 of 14	1		ENSP00000430251.1
EXO1	ENST00000521202.2	c.303+2630C>G		intron_variant	Intron 1 of 2	5		ENSP00000428326.1

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 v4.3

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;T;.
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.86
FATHMM_MKL	Benign	0.098	N
LIST_S2	Benign	0.51	.;T;T
M_CAP	Benign	0.0065	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.34	N;N;N
PhyloP100		0.58
PrimateAI	Benign	0.21	T
PROVEAN	Benign	-0.69	N;N;N
REVEL	Benign	0.032
Sift	Benign	0.28	T;T;T
Sift4G	Benign	0.43	T;T;T
Polyphen		0.012	B;B;B
Vest4		0.14
MutPred		0.18		Loss of stability (P = 0.0172);Loss of stability (P = 0.0172);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;