1-241852407-A-G

Position:

• chr1-241852407-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_130398.4(EXO1):​c.277A>G​(p.Arg93Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,597,900 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts 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 0.0089 (19 hom., cov: 32)
  • Exomes 𝑓: 0.00090 (23 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.14

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009332746).
• BP6: Variant 1-241852407-A-G is Benign according to our data. Variant chr1-241852407-A-G is described in ClinVar as [Benign]. Clinvar id is 782400.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00887 (1351/152346) while in subpopulation AFR AF= 0.0314 (1307/41574). AF 95% confidence interval is 0.03. There are 19 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 19 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.277A>G	p.Arg93Gly	missense_variant	5/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.277A>G	p.Arg93Gly	missense_variant	5/16	1	NM_130398.4	P2

Frequencies

GnomAD3 genomes AF: 0.00887 AC: 1351 AN: 152228 Hom.: 19 Cov.: 32

Gnomad AFR AF: 0.0315

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00478

GnomAD3 exomes AF: 0.00232 AC: 580 AN: 250464 Hom.: 15 AF XY: 0.00162 AC XY: 219 AN XY: 135520

Gnomad AFR exome AF: 0.0321

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000897 AC: 1297 AN: 1445554 Hom.: 23 Cov.: 26 AF XY: 0.000773 AC XY: 557 AN XY: 720214

Gnomad4 AFR exome AF: 0.0337

Gnomad4 AMR exome AF: 0.00152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000349

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000118

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00887 AC: 1351 AN: 152346 Hom.: 19 Cov.: 32 AF XY: 0.00846 AC XY: 630 AN XY: 74498

Gnomad4 AFR AF: 0.0314

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00473

Alfa AF: 0.00156 Hom.: 8

Bravo AF: 0.0104

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0329 AC: 145

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00277 AC: 336

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

EXO1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 20, 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). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.69
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.41	T;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
MetaRNN	Benign	0.0093	T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-6.1	D;D;D;D
REVEL	Benign	0.23
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;T
Polyphen		1.0	D;D;D;.
Vest4		0.74
MVP		0.78
MPC		0.36
ClinPred		0.066	T
GERP RS		5.0
Varity_R		0.70
gMVP		0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs4149865; hg19: chr1-242015709; COSMIC: COSV105266949; COSMIC: COSV105266949;