1-241878999-G-C

Position:

• chr1-241878999-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_130398.4(EXO1):​c.1765G>C​(p.Glu589Gln) 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. 15/21 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. E589K) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0230

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053917825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
EXO1	NM_130398.4	c.1765G>C	p.Glu589Gln	missense_variant	13/16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.1765G>C	p.Glu589Gln	missense_variant	13/16	1	NM_130398.4	ENSP00000355506	P2
EXO1	ENST00000348581.9	c.1765G>C	p.Glu589Gln	missense_variant	11/14	1		ENSP00000311873	P2
EXO1	ENST00000518483.5	c.1765G>C	p.Glu589Gln	missense_variant	11/14	1		ENSP00000430251	A2
EXO1	ENST00000521202.2			upstream_gene_variant		5		ENSP00000428326

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 39

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.44
DANN	Benign	0.76
DEOGEN2	Benign	0.15	T;T;.
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.19	.;T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.054	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.20	N;N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-0.68	N;N;N
REVEL	Benign	0.033
Sift	Benign	0.23	T;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.0	B;B;B
Vest4		0.078
MutPred		0.073		Loss of ubiquitination at K592 (P = 0.0457);Loss of ubiquitination at K592 (P = 0.0457);Loss of ubiquitination at K592 (P = 0.0457);
MVP		0.21
MPC		0.049
ClinPred		0.051	T
GERP RS		-3.3
Varity_R		0.030
gMVP		0.23

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

Publications

LitVar

Other links and lift over

dbSNP: rs1047840; hg19: chr1-242042301;