1-241858517-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 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

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 Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.555G>T	p.Lys185Asn	missense_variant	8/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.555G>T	p.Lys185Asn	missense_variant	8/16	1	NM_130398.4	P2

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

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: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

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

Aug 16, 2021

The c.555G>T (p.K185N) alteration is located in exon 6 (coding exon 5) of the EXO1 gene. This alteration results from a G to T substitution at nucleotide position 555, causing the lysine (K) at amino acid position 185 to be replaced by an asparagine (N). 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	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;T;D;.;T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Benign	0.077	D
MetaRNN	Uncertain	0.67	D;D;D;D;D
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.5	L;.;L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D
REVEL	Uncertain	0.42
Sift	Pathogenic	0.0	D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;.;D;D;.
Vest4		0.90
MutPred		0.68		Gain of ubiquitination at K180 (P = 0.0745);.;Gain of ubiquitination at K180 (P = 0.0745);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

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

Publications

LitVar

Other links and lift over

dbSNP: rs1661189860; hg19: chr1-242021819;