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rs25487

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_StrongBA1

The NM_006297.3(XRCC1):c.1196A>G(p.Gln399Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.658 in 1,613,104 control chromosomes in the GnomAD database, including 351,454 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.71 ( 39067 hom., cov: 33)
Exomes 𝑓: 0.65 ( 312387 hom. )

Consequence

XRCC1
NM_006297.3 missense

Scores

1
14

Clinical Significance

drug response reviewed by expert panel B:2O:1

Conservation

PhyloP100: 1.98
Variant links:
Genes affected
XRCC1 (HGNC:12828): (X-ray repair cross complementing 1) The protein encoded by this gene is involved in the efficient repair of DNA single-strand breaks formed by exposure to ionizing radiation and alkylating agents. This protein interacts with DNA ligase III, polymerase beta and poly (ADP-ribose) polymerase to participate in the base excision repair pathway. It may play a role in DNA processing during meiogenesis and recombination in germ cells. A rare microsatellite polymorphism in this gene is associated with cancer in patients of varying radiosensitivity. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=6.525281E-7).
BP6
Variant 19-43551574-T-C is Benign according to our data. Variant chr19-43551574-T-C is described in ClinVar as [drug_response]. Clinvar id is 225976.Status of the report is reviewed_by_expert_panel, 3 stars. We mark this variant Likely_benign, oryginal submissions are: {Benign=2, drug_response=1}.
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.845 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
XRCC1NM_006297.3 linkuse as main transcriptc.1196A>G p.Gln399Arg missense_variant 10/17 ENST00000262887.10

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
XRCC1ENST00000262887.10 linkuse as main transcriptc.1196A>G p.Gln399Arg missense_variant 10/171 NM_006297.3 P1
XRCC1ENST00000543982.5 linkuse as main transcriptc.1103A>G p.Gln368Arg missense_variant 9/162
XRCC1ENST00000597811.5 linkuse as main transcriptc.*310A>G 3_prime_UTR_variant, NMD_transcript_variant 7/75

Frequencies

GnomAD3 genomes
AF:
0.711
AC:
108110
AN:
152018
Hom.:
39012
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.852
Gnomad AMI
AF:
0.590
Gnomad AMR
AF:
0.689
Gnomad ASJ
AF:
0.596
Gnomad EAS
AF:
0.738
Gnomad SAS
AF:
0.652
Gnomad FIN
AF:
0.695
Gnomad MID
AF:
0.734
Gnomad NFE
AF:
0.642
Gnomad OTH
AF:
0.712
GnomAD3 exomes
AF:
0.681
AC:
170473
AN:
250468
Hom.:
58636
AF XY:
0.673
AC XY:
91132
AN XY:
135456
show subpopulations
Gnomad AFR exome
AF:
0.855
Gnomad AMR exome
AF:
0.735
Gnomad ASJ exome
AF:
0.618
Gnomad EAS exome
AF:
0.742
Gnomad SAS exome
AF:
0.648
Gnomad FIN exome
AF:
0.688
Gnomad NFE exome
AF:
0.643
Gnomad OTH exome
AF:
0.662
GnomAD4 exome
AF:
0.652
AC:
952451
AN:
1460968
Hom.:
312387
Cov.:
39
AF XY:
0.652
AC XY:
473566
AN XY:
726870
show subpopulations
Gnomad4 AFR exome
AF:
0.857
Gnomad4 AMR exome
AF:
0.730
Gnomad4 ASJ exome
AF:
0.613
Gnomad4 EAS exome
AF:
0.741
Gnomad4 SAS exome
AF:
0.647
Gnomad4 FIN exome
AF:
0.691
Gnomad4 NFE exome
AF:
0.638
Gnomad4 OTH exome
AF:
0.667
GnomAD4 genome
AF:
0.711
AC:
108216
AN:
152136
Hom.:
39067
Cov.:
33
AF XY:
0.713
AC XY:
53053
AN XY:
74358
show subpopulations
Gnomad4 AFR
AF:
0.852
Gnomad4 AMR
AF:
0.689
Gnomad4 ASJ
AF:
0.596
Gnomad4 EAS
AF:
0.738
Gnomad4 SAS
AF:
0.652
Gnomad4 FIN
AF:
0.695
Gnomad4 NFE
AF:
0.642
Gnomad4 OTH
AF:
0.710
Alfa
AF:
0.656
Hom.:
48415
Bravo
AF:
0.719
TwinsUK
AF:
0.626
AC:
2320
ALSPAC
AF:
0.646
AC:
2489
ESP6500AA
AF:
0.845
AC:
3723
ESP6500EA
AF:
0.640
AC:
5501
ExAC
AF:
0.682
AC:
82838
Asia WGS
AF:
0.709
AC:
2466
AN:
3478
EpiCase
AF:
0.648
EpiControl
AF:
0.650

ClinVar

Significance: drug response
Submissions summary: Benign:2Other:1
Revision: reviewed by expert panel
LINK: link

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 26 Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabDec 05, 2021- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingGeneDxJul 31, 2020This variant is associated with the following publications: (PMID: 21427728, 15113441, 19481337, 11782372, 23479765, 14630517, 21843798, 22053659, 22951806, 24176953, 22224629, 22106831, 23360319, 21987112, 21928248, 18641418, 22193858, 19012493, 22525558, 22712837, 19880550, 22302399, 22983827, 21617750, 20431719, 23499241, 19465687, 20385586, 18357393, 21647176, 19051060, 23055018, 17961713, 22868082, 22568010, 19428062, 11104903, 24205020) -
Platinum compounds response - Efficacy Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Efficacy

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.053
BayesDel_addAF
Benign
-0.80
T
BayesDel_noAF
Benign
-0.77
Cadd
Benign
15
Dann
Benign
0.13
Eigen
Benign
-0.60
Eigen_PC
Benign
-0.45
FATHMM_MKL
Benign
0.41
N
MetaRNN
Benign
6.5e-7
T;T
MetaSVM
Benign
-0.98
T
MutationTaster
Benign
1.0
P;P
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
2.1
N;N
REVEL
Benign
0.072
Sift
Benign
1.0
T;T
Sift4G
Benign
0.88
T;T
Polyphen
0.0
.;B
Vest4
0.057
MPC
0.23
ClinPred
0.0059
T
GERP RS
4.1
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
gMVP
0.15

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: rs25487; hg19: chr19-44055726; COSMIC: COSV53447249; COSMIC: COSV53447249; API