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GeneBe

1-241850524-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_130398.4(EXO1):c.99C>T(p.Cys33=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00246 in 1,613,898 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 49 hom., cov: 32)
Exomes 𝑓: 0.0013 ( 44 hom. )

Consequence

EXO1
NM_130398.4 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.0120
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4
?
    BP4 - Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc.)
Computational evidence support a benign effect (BayesDel_noAF=-0.48).
BP6
?
    BP6 - Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation
Variant 1-241850524-C-T is Benign according to our data. Variant chr1-241850524-C-T is described in ClinVar as [Benign]. Clinvar id is 767769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
?
    BP7 - A synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence nor the creation of a new splice site AND the nucleotide is not highly conserved
Synonymous conserved (PhyloP=0.012 with no splicing effect.
BS1
?
    BS1 - Allele frequency is greater than expected for disorder
Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0133 (2021/152292) while in subpopulation AFR AF= 0.0465 (1934/41560). AF 95% confidence interval is 0.0448. There are 49 homozygotes in gnomad4. There are 976 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
    BS2 - Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age
High Homozygotes in GnomAd at 49 AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
EXO1NM_130398.4 linkuse as main transcriptc.99C>T p.Cys33= synonymous_variant 4/16 ENST00000366548.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
EXO1ENST00000366548.8 linkuse as main transcriptc.99C>T p.Cys33= synonymous_variant 4/161 NM_130398.4 P2Q9UQ84-1

Frequencies

GnomAD3 genomes
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0132
AC:
2016
AN:
152174
Hom.:
49
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0465
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00426
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.0100
GnomAD3 exomes
AF:
0.00324
AC:
815
AN:
251460
Hom.:
15
AF XY:
0.00230
AC XY:
312
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.0442
Gnomad AMR exome
AF:
0.00231
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000131
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000615
Gnomad OTH exome
AF:
0.000815
GnomAD4 exome
AF:
0.00134
AC:
1957
AN:
1461606
Hom.:
44
Cov.:
31
AF XY:
0.00110
AC XY:
797
AN XY:
727122
show subpopulations
Gnomad4 AFR exome
AF:
0.0484
Gnomad4 AMR exome
AF:
0.00235
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.000151
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000171
Gnomad4 OTH exome
AF:
0.00318
GnomAD4 genome
?
    Genome Aggregation Database, over 76,156 genomes
AF:
0.0133
AC:
2021
AN:
152292
Hom.:
49
Cov.:
32
AF XY:
0.0131
AC XY:
976
AN XY:
74456
show subpopulations
Gnomad4 AFR
AF:
0.0465
Gnomad4 AMR
AF:
0.00418
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00992
Alfa
AF:
0.00744
Hom.:
15
Bravo
AF:
0.0153
Asia WGS
AF:
0.00202
AC:
7
AN:
3478
EpiCase
AF:
0.000164
EpiControl
AF:
0.00

ClinVar

Significance: Benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

EXO1-related disorder Benign:1
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact SciencesFeb 16, 2019This 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 submitterclinical testingInvitaeMay 21, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.48
Cadd
Benign
8.3
Dann
Benign
0.59

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs4149857; hg19: chr1-242013826; API