Genetic Variant XRCC1:p.Arg280His (chr19-43552260-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_006297.3(XRCC1):c.839G>A(p.Arg280His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0528 in 1,605,884 control chromosomes in the GnomAD database, including 2,668 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.051 ( 262 hom., cov: 32)

Exomes 𝑓: 0.053 ( 2406 hom. )

Consequence

XRCC1
NM_006297.3 missense

Scores

Clinical Significance

association no assertion criteria provided O:1

Conservation

PhyloP100: 1.15

Publications

489 publications found

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]

XRCC1 Gene-Disease associations (from GenCC):

head and neck cancer
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics
spinocerebellar ataxia, autosomal recessive 26
Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

XRCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0028283298).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0898 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.839G>A	p.Arg280His	missense_variant	Exon 9 of 17	ENST00000262887.10	NP_006288.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10 link	c.839G>A	p.Arg280His	missense_variant	Exon 9 of 17	1	NM_006297.3	ENSP00000262887.5

Frequencies

GnomAD3 genomes

AF:

0.0512

AC:

7790

AN:

152010

Hom.:

262

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0309

Gnomad AMI

AF:

0.0198

Gnomad AMR

AF:

0.0827

Gnomad ASJ

AF:

0.0582

Gnomad EAS

AF:

0.0968

Gnomad SAS

AF:

0.0962

Gnomad FIN

AF:

0.0704

Gnomad MID

AF:

0.171

Gnomad NFE

AF:

0.0462

Gnomad OTH

AF:

0.0589

GnomAD2 exomes

AF:

0.0711

AC:

16710

AN:

235054

AF XY:

0.0706

show subpopulations

Gnomad AFR exome

AF:

0.0291

Gnomad AMR exome

AF:

0.121

Gnomad ASJ exome

AF:

0.0607

Gnomad EAS exome

AF:

0.110

Gnomad FIN exome

AF:

0.0746

Gnomad NFE exome

AF:

0.0499

Gnomad OTH exome

AF:

0.0720

GnomAD4 exome

AF:

0.0529

AC:

76924

AN:

1453756

Hom.:

2406

Cov.:

AF XY:

0.0539

AC XY:

38963

AN XY:

722974

show subpopulations

African (AFR)

AF:

0.0272

AC:

905

AN:

33268

American (AMR)

AF:

0.114

AC:

4955

AN:

43534

Ashkenazi Jewish (ASJ)

AF:

0.0612

AC:

1588

AN:

25966

East Asian (EAS)

AF:

0.0917

AC:

3607

AN:

39356

South Asian (SAS)

AF:

0.0887

AC:

7605

AN:

85708

European-Finnish (FIN)

AF:

0.0740

AC:

3774

AN:

51014

Middle Eastern (MID)

AF:

0.135

AC:

779

AN:

5758

European-Non Finnish (NFE)

AF:

0.0453

AC:

50260

AN:

1109032

Other (OTH)

AF:

0.0574

AC:

3451

AN:

60120

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

4357

8714

13070

17427

21784

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1996

3992

5988

7984

9980

<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:

0.0512

AC:

7787

AN:

152128

Hom.:

262

Cov.:

AF XY:

0.0551

AC XY:

4093

AN XY:

74348

show subpopulations

African (AFR)

AF:

0.0308

AC:

1277

AN:

41498

American (AMR)

AF:

0.0827

AC:

1265

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0582

AC:

202

AN:

3472

East Asian (EAS)

AF:

0.0968

AC:

500

AN:

5164

South Asian (SAS)

AF:

0.0963

AC:

465

AN:

4828

European-Finnish (FIN)

AF:

0.0704

AC:

746

AN:

10600

Middle Eastern (MID)

AF:

0.177

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0462

AC:

3141

AN:

67960

Other (OTH)

AF:

0.0573

AC:

121

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

372

745

1117

1490

1862

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

180

270

360

450

<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:

0.0502

Hom.:

823

Bravo

AF:

0.0526

TwinsUK

AF:

0.0388

AC:

144

ALSPAC

AF:

0.0475

AC:

183

ESP6500AA

AF:

0.0318

AC:

140

ESP6500EA

AF:

0.0484

AC:

416

ExAC

AF:

0.0656

AC:

7950

Asia WGS

AF:

0.0930

AC:

323

AN:

3478

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Laryngeal squamous cell carcinoma

Other:1

Jun 16, 2022

Department Of Otolaryngology, First Affiliated Hospital Of Xinjiang Medical University

Significance:association

Review Status:no assertion criteria provided

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.079

BayesDel_addAF

Benign

-0.65

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0

.;T;.

Eigen

Benign

-0.84

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.070

LIST_S2

Benign

0.0

.;T;T

MetaRNN

Benign

0.0028

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

.;.;.

PhyloP100

1.1

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N;.

REVEL

Benign

0.036

Sift

Benign

0.12

T;T;.

Sift4G

Benign

0.40

T;T;T

Vest4

0.15

ClinPred

0.0072

GERP RS

-0.70

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

gMVP

0.32

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over