1-241852356-G-A

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.226G>A(p.Val76Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00127 in 1,585,864 control chromosomes in the GnomAD database, including 25 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 0.0067 (10 hom., cov: 32)
  • Exomes 𝑓: 0.00069 (15 hom.)
• Consequence: EXO1 NM_130398.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.26

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=0.01624602).
• BP6: Variant 1-241852356-G-A is Benign according to our data. Variant chr1-241852356-G-A is described in ClinVar as [Benign]. Clinvar id is 784980.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 = 0.00675 (1027/152192) while in subpopulation AFR AF= 0.0236 (982/41528). AF 95% confidence interval is 0.0224. There are 10 homozygotes in gnomad4. There are 491 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 10 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
EXO1	NM_130398.4	c.226G>A	p.Val76Ile	missense_variant	5/16	ENST00000366548.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
EXO1	ENST00000366548.8	c.226G>A	p.Val76Ile	missense_variant	5/16	1	NM_130398.4	P2

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1026 AN: 152076 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.0237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00175 AC: 439 AN: 250976 Hom.: 11 AF XY: 0.00132 AC XY: 179 AN XY: 135688

Gnomad AFR exome AF: 0.0245

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000686 AC: 984 AN: 1433672 Hom.: 15 Cov.: 25 AF XY: 0.000534 AC XY: 382 AN XY: 715202

Gnomad4 AFR exome AF: 0.0254

Gnomad4 AMR exome AF: 0.000716

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0000700

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000258

Gnomad4 OTH exome AF: 0.00123

GnomAD4 genome AF: 0.00675 AC: 1027 AN: 152192 Hom.: 10 Cov.: 32 AF XY: 0.00660 AC XY: 491 AN XY: 74410

Gnomad4 AFR AF: 0.0236

Gnomad4 AMR AF: 0.00164

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00175 Hom.: 6

Bravo AF: 0.00737

ESP6500AA AF: 0.0191 AC: 84

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00207 AC: 251

Asia WGS AF: 0.000866 AC: 3 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

Jul 12, 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

Feb 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.31
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.20	T;T;.;T
Eigen	Benign	0.020
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.91	D
MetaRNN	Benign	0.016	T;T;T;T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M;M;M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.84	N;N;N;N
REVEL	Benign	0.20
Sift	Benign	0.10	T;T;T;T
Sift4G	Benign	0.072	T;T;T;D
Polyphen		0.82	P;P;P;.
Vest4		0.30
MVP		0.56
MPC		0.072
ClinPred		0.041	T
GERP RS		2.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.094
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs4149864; hg19: chr1-242015658; COSMIC: COSV62216355; COSMIC: COSV62216355;