rs25487

Positions:

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. 12/18 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

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]

XRCC1 links:

Genome browser will be placed here

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: {drug_response=1, Benign=2}.

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
XRCC1	NM_006297.3 linkuse as main transcript	c.1196A>G	p.Gln399Arg	missense_variant	10/17	ENST00000262887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris
XRCC1	ENST00000262887.10 linkuse as main transcript	c.1196A>G	p.Gln399Arg	missense_variant	10/17	1	NM_006297.3	P1
XRCC1	ENST00000543982.5 linkuse as main transcript	c.1103A>G	p.Gln368Arg	missense_variant	9/16	2
XRCC1	ENST00000597811.5 linkuse as main transcript	c.*310A>G		3_prime_UTR_variant, NMD_transcript_variant	7/7	5

Frequencies

GnomAD3 genomes

AF:

0.711

AC:

108110

AN:

152018

Hom.:

39012

Cov.:

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.:

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.:

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 submitter

clinical testing

Genome-Nilou Lab

Dec 05, 2021

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 31, 2020

This 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 panel

curation

PharmGKB

Mar 24, 2021

PharmGKB 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

BayesDel_noAF

Benign

-0.77

CADD

Benign

DANN

Benign

0.13

DEOGEN2

Benign

0.0072

.;T

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.45

FATHMM_MKL

Benign

0.41

LIST_S2

Benign

0.029

.;T

MetaRNN

Benign

6.5e-7

T;T

MetaSVM

Benign

-0.98

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.72

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

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over