rs25487

chr19-43551574-T-Cchr19-43551574-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Strong BA1

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
• Clinical Significance: drug response reviewed by expert panel B:2 O:1
• Conservation: PhyloP100: 1.98

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]

ACMG classification

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	c.1196A>G	p.Gln399Arg	missense_variant	10/17	ENST00000262887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC1	ENST00000262887.10	c.1196A>G	p.Gln399Arg	missense_variant	10/17	1	NM_006297.3	P1
XRCC1	ENST00000543982.5	c.1103A>G	p.Gln368Arg	missense_variant	9/16	2
XRCC1	ENST00000597811.5	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.: 33

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

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

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

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:2 Other:1

Revision: reviewed by expert panel

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	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

Other links and lift over

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