NM_130398.4:c.555G>T

Variant names:

• chr1-241858517-G-T
• rs1661189860
• NM_130398.4:c.555G>T

Variant summary

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

The NM_130398.4(EXO1):​c.555G>T​(p.Lys185Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,166 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.46
• Publications: 0 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_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.555G>T	p.Lys185Asn	missense	Exon 8 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.555G>T	p.Lys185Asn	missense	Exon 6 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.555G>T	p.Lys185Asn	missense	Exon 7 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.555G>T	p.Lys185Asn	missense	Exon 8 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.555G>T	p.Lys185Asn	missense	Exon 6 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.555G>T	p.Lys185Asn	missense	Exon 6 of 14	ENSP00000430251.1	Q9UQ84-4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461166 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726904

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111374

Other (OTH) AF: 0.00 AC: 0 AN: 60378

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.64	D
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.67	D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L
PhyloP100		3.5
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.68		Gain of ubiquitination at K180 (P = 0.0745)
MVP		0.64
MPC		0.35
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.97
gMVP		0.89
Mutation Taster		=14/86	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1661189860; hg19: chr1-242021819;