rs4149963

Positions:

• chr1-241872080-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_130398.4(EXO1):​c.1316C>T​(p.Thr439Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0852 in 1,612,702 control chromosomes in the GnomAD database, including 7,709 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.078 (720 hom., cov: 31)
  • Exomes 𝑓: 0.086 (6989 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.611

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005331129).
• BP6: Variant 1-241872080-C-T is Benign according to our data. Variant chr1-241872080-C-T is described in ClinVar as [Benign]. Clinvar id is 3059408.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.1316C>T	p.Thr439Met	missense_variant	12/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.1316C>T	p.Thr439Met	missense_variant	12/16	1	NM_130398.4	P2
EXO1	ENST00000348581.9	c.1316C>T	p.Thr439Met	missense_variant	10/14	1		P2
EXO1	ENST00000518483.5	c.1316C>T	p.Thr439Met	missense_variant	10/14	1		A2

Frequencies

GnomAD3 genomes AF: 0.0779 AC: 11822 AN: 151810 Hom.: 715 Cov.: 31

Gnomad AFR AF: 0.0205

Gnomad AMI AF: 0.0659

Gnomad AMR AF: 0.194

Gnomad ASJ AF: 0.0539

Gnomad EAS AF: 0.0851

Gnomad SAS AF: 0.0951

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0817

Gnomad OTH AF: 0.0850

GnomAD3 exomes AF: 0.112 AC: 27982 AN: 250940 Hom.: 2632 AF XY: 0.105 AC XY: 14204 AN XY: 135746

Gnomad AFR exome AF: 0.0182

Gnomad AMR exome AF: 0.310

Gnomad ASJ exome AF: 0.0475

Gnomad EAS exome AF: 0.0749

Gnomad SAS exome AF: 0.0942

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0821

Gnomad OTH exome AF: 0.101

GnomAD4 exome AF: 0.0860 AC: 125629 AN: 1460774 Hom.: 6989 Cov.: 32 AF XY: 0.0858 AC XY: 62370 AN XY: 726780

Gnomad4 AFR exome AF: 0.0148

Gnomad4 AMR exome AF: 0.295

Gnomad4 ASJ exome AF: 0.0487

Gnomad4 EAS exome AF: 0.0968

Gnomad4 SAS exome AF: 0.0939

Gnomad4 FIN exome AF: 0.111

Gnomad4 NFE exome AF: 0.0790

Gnomad4 OTH exome AF: 0.0771

GnomAD4 genome AF: 0.0778 AC: 11827 AN: 151928 Hom.: 720 Cov.: 31 AF XY: 0.0811 AC XY: 6026 AN XY: 74258

Gnomad4 AFR AF: 0.0204

Gnomad4 AMR AF: 0.194

Gnomad4 ASJ AF: 0.0539

Gnomad4 EAS AF: 0.0851

Gnomad4 SAS AF: 0.0952

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0817

Gnomad4 OTH AF: 0.0841

Alfa AF: 0.0819 Hom.: 1433

Bravo AF: 0.0831

TwinsUK AF: 0.0707 AC: 262

ALSPAC AF: 0.0778 AC: 300

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.0769 AC: 661

ExAC AF: 0.102 AC: 12430

Asia WGS AF: 0.0920 AC: 320 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

EXO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 04, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.69	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	6.8
DANN	Benign	0.95
DEOGEN2	Benign	0.21	T;T;.
Eigen	Benign	-0.60
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.38	.;T;T
MetaRNN	Benign	0.0053	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M;M
MutationTaster	Benign	1.0	P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Benign	0.046
Sift	Benign	0.055	T;T;T
Sift4G	Benign	0.064	T;T;T
Polyphen		0.014	B;B;B
Vest4		0.13
MPC		0.059
ClinPred		0.0058	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.023
gMVP		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4149963; hg19: chr1-242035382; COSMIC: COSV62216899;