1-241858683-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.721G>C(p.Val241Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.58

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=0.046589494).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.721G>C	p.Val241Leu	missense_variant	8/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.721G>C	p.Val241Leu	missense_variant	8/16	1	NM_130398.4	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461580 Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3 AN XY: 727132

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 21, 2023

The c.721G>C (p.V241L) alteration is located in exon 6 (coding exon 5) of the EXO1 gene. This alteration results from a G to C substitution at nucleotide position 721, causing the valine (V) at amino acid position 241 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	16
Dann	Benign	0.38
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.48
FATHMM_MKL	Uncertain	0.77	D
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-3.2	N;N;N
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.69	N;N;N
REVEL	Benign	0.056
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0010	B;B;B
Vest4		0.25
MutPred		0.49		Loss of methylation at K240 (P = 0.0628);Loss of methylation at K240 (P = 0.0628);Loss of methylation at K240 (P = 0.0628);
MVP		0.18
MPC		0.048
ClinPred		0.10	T
GERP RS		3.4
Varity_R		0.12
gMVP		0.59

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: rs770549019; hg19: chr1-242021985;