rs4149864

Variant names:

• chr1-241852356-G-A
• rs4149864
• NM_130398.4:c.226G>A

Your query was ambiguous. Multiple possible variants found:

• chr1-241852356-G-A
• chr1-241852356-G-T

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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:3
• Conservation: PhyloP100: 4.26
• Publications: 7 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 -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 VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1027 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_130398.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	NM_130398.4	MANE Select	c.226G>A	p.Val76Ile	missense	Exon 5 of 16	NP_569082.2	Q9UQ84-1
	EXO1	NM_006027.4		c.226G>A	p.Val76Ile	missense	Exon 3 of 14	NP_006018.4	Q9UQ84-1
	EXO1	NM_001319224.2		c.226G>A	p.Val76Ile	missense	Exon 4 of 15	NP_001306153.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EXO1	ENST00000366548.8	TSL:1 MANE Select	c.226G>A	p.Val76Ile	missense	Exon 5 of 16	ENSP00000355506.3	Q9UQ84-1
	EXO1	ENST00000348581.9	TSL:1	c.226G>A	p.Val76Ile	missense	Exon 3 of 14	ENSP00000311873.5	Q9UQ84-1
	EXO1	ENST00000518483.5	TSL:1	c.226G>A	p.Val76Ile	missense	Exon 3 of 14	ENSP00000430251.1	Q9UQ84-4

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

GnomAD2 exomes AF: 0.00175 AC: 439 AN: 250976 AF XY: 0.00132

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 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

African (AFR) AF: 0.0254 AC: 836 AN: 32874

American (AMR) AF: 0.000716 AC: 32 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25952

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39516

South Asian (SAS) AF: 0.0000700 AC: 6 AN: 85698

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5722

European-Non Finnish (NFE) AF: 0.0000258 AC: 28 AN: 1086916

Other (OTH) AF: 0.00123 AC: 73 AN: 59390

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

African (AFR) AF: 0.0236 AC: 982 AN: 41528

American (AMR) AF: 0.00164 AC: 25 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68004

Other (OTH) AF: 0.00569 AC: 12 AN: 2110

Alfa AF: 0.00334 Hom.: 11

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	EXO1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	0.020
Eigen_PC	Benign	-0.017
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.016	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		4.3
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.20
Sift	Benign	0.10	T
Sift4G	Benign	0.072	T
Polyphen		0.82	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
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs4149864; hg19: chr1-242015658; COSMIC: COSV62216355; COSMIC: COSV62216355;