chr1-241872080-C-T

Variant names:

• chr1-241872080-C-T
• rs4149963
• NM_130398.4:c.1316C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.078 (720 hom., cov: 31)
  • Exomes 𝑓: 0.086 (6989 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.611
• Publications: 45 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: Benign. The variant received -13 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 VariationId is 3059408.Status of the report is no_assertion_criteria_provided, 0 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 rank	MANE	Protein	UniProt
EXO1	NM_130398.4	c.1316C>T	p.Thr439Met	missense_variant	Exon 12 of 16	ENST00000366548.8	NP_569082.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
EXO1	ENST00000366548.8	c.1316C>T	p.Thr439Met	missense_variant	Exon 12 of 16	1	NM_130398.4	ENSP00000355506.3
EXO1	ENST00000348581.9	c.1316C>T	p.Thr439Met	missense_variant	Exon 10 of 14	1		ENSP00000311873.5
EXO1	ENST00000518483.5	c.1316C>T	p.Thr439Met	missense_variant	Exon 10 of 14	1		ENSP00000430251.1

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

GnomAD2 exomes AF: 0.112 AC: 27982 AN: 250940 AF XY: 0.105

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 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

African (AFR) AF: 0.0148 AC: 497 AN: 33472

American (AMR) AF: 0.295 AC: 13199 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.0487 AC: 1273 AN: 26120

East Asian (EAS) AF: 0.0968 AC: 3841 AN: 39676

South Asian (SAS) AF: 0.0939 AC: 8097 AN: 86228

European-Finnish (FIN) AF: 0.111 AC: 5920 AN: 53410

Middle Eastern (MID) AF: 0.0567 AC: 327 AN: 5764

European-Non Finnish (NFE) AF: 0.0790 AC: 87821 AN: 1111042

Other (OTH) AF: 0.0771 AC: 4654 AN: 60358

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

African (AFR) AF: 0.0204 AC: 847 AN: 41438

American (AMR) AF: 0.194 AC: 2960 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0539 AC: 187 AN: 3470

East Asian (EAS) AF: 0.0851 AC: 440 AN: 5168

South Asian (SAS) AF: 0.0952 AC: 458 AN: 4810

European-Finnish (FIN) AF: 0.108 AC: 1131 AN: 10518

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0817 AC: 5554 AN: 67968

Other (OTH) AF: 0.0841 AC: 177 AN: 2104

Alfa AF: 0.0815 Hom.: 2054

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: no assertion criteria provided

Submissions by phenotype

EXO1-related disorder Benign:1

Nov 04, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		0.61
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
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4149963; hg19: chr1-242035382; COSMIC: COSV62216899;