Genetic Variant EXO1:c.2406-146T>G (chr1-241889319-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_130398.4(EXO1):c.2406-146T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.415 in 710,212 control chromosomes in the GnomAD database, including 62,119 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.40 ( 12158 hom., cov: 32)

Exomes 𝑓: 0.42 ( 49961 hom. )

Consequence

EXO1
NM_130398.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.217

Publications

8 publications found

Variant links:

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

EXO1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.478 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EXO1	NM_130398.4	MANE Select	c.2406-146T>G	intron	N/A	NP_569082.2
EXO1	NM_006027.4		c.2406-146T>G	intron	N/A	NP_006018.4
EXO1	NM_001319224.2		c.2403-146T>G	intron	N/A	NP_001306153.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
EXO1	ENST00000366548.8	TSL:1 MANE Select	c.2406-146T>G	intron	N/A	ENSP00000355506.3
EXO1	ENST00000348581.9	TSL:1	c.2406-146T>G	intron	N/A	ENSP00000311873.5
EXO1	ENST00000518483.5	TSL:1	c.2406-148T>G	intron	N/A	ENSP00000430251.1

Frequencies

GnomAD3 genomes

AF:

0.396

AC:

60158

AN:

151908

Hom.:

12151

Cov.:

show subpopulations

Gnomad AFR

AF:

0.312

Gnomad AMI

AF:

0.471

Gnomad AMR

AF:

0.487

Gnomad ASJ

AF:

0.439

Gnomad EAS

AF:

0.464

Gnomad SAS

AF:

0.384

Gnomad FIN

AF:

0.383

Gnomad MID

AF:

0.383

Gnomad NFE

AF:

0.420

Gnomad OTH

AF:

0.417

GnomAD4 exome

AF:

0.420

AC:

234338

AN:

558186

Hom.:

49961

AF XY:

0.418

AC XY:

123776

AN XY:

295958

show subpopulations

African (AFR)

AF:

0.312

AC:

4648

AN:

14874

American (AMR)

AF:

0.506

AC:

14401

AN:

28464

Ashkenazi Jewish (ASJ)

AF:

0.456

AC:

7807

AN:

17104

East Asian (EAS)

AF:

0.448

AC:

14089

AN:

31470

South Asian (SAS)

AF:

0.388

AC:

21174

AN:

54544

European-Finnish (FIN)

AF:

0.386

AC:

13368

AN:

34660

Middle Eastern (MID)

AF:

0.375

AC:

861

AN:

2294

European-Non Finnish (NFE)

AF:

0.422

AC:

145625

AN:

345170

Other (OTH)

AF:

0.418

AC:

12365

AN:

29606

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

6839

13678

20518

27357

34196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1624

3248

4872

6496

8120

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.396

AC:

60197

AN:

152026

Hom.:

12158

Cov.:

AF XY:

0.396

AC XY:

29448

AN XY:

74300

show subpopulations

African (AFR)

AF:

0.312

AC:

12965

AN:

41494

American (AMR)

AF:

0.487

AC:

7425

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

1521

AN:

3464

East Asian (EAS)

AF:

0.463

AC:

2392

AN:

5168

South Asian (SAS)

AF:

0.385

AC:

1853

AN:

4818

European-Finnish (FIN)

AF:

0.383

AC:

4046

AN:

10552

Middle Eastern (MID)

AF:

0.384

AC:

113

AN:

294

European-Non Finnish (NFE)

AF:

0.420

AC:

28576

AN:

67966

Other (OTH)

AF:

0.417

AC:

878

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1853

3707

5560

7414

9267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

558

1116

1674

2232

2790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.395

Hom.:

6948

Bravo

AF:

0.406

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.80

CADD

Benign

2.1

(source)

DANN

Benign

0.43

PhyloP100

0.22

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over