rs2307187

chr19-43575459-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_006297.3(XRCC1):c.-1C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.015 in 1,612,136 control chromosomes in the GnomAD database, including 271 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.021 (48 hom., cov: 32)
  • Exomes 𝑓: 0.014 (223 hom.)
• Consequence: XRCC1 NM_006297.3 5_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.46

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 19-43575459-G-A is Benign according to our data. Variant chr19-43575459-G-A is described in ClinVar as [Benign]. Clinvar id is 3060460.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAdExome4 highest subpopulation (MID) allele frequency at 95% confidence interval = 0.0512 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC1	NM_006297.3	c.-1C>T		5_prime_UTR_variant	1/17	ENST00000262887.10
PINLYP	XM_047438830.1			upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC1	ENST00000262887.10	c.-1C>T		5_prime_UTR_variant	1/17	1	NM_006297.3	P1
	ENST00000600242.1	n.387G>A		non_coding_transcript_exon_variant	2/2	4

Frequencies

GnomAD3 genomes AF: 0.0214 AC: 3256 AN: 152194 Hom.: 48 Cov.: 32

Gnomad AFR AF: 0.0364

Gnomad AMI AF: 0.0197

Gnomad AMR AF: 0.0285

Gnomad ASJ AF: 0.0222

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0168

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0234

GnomAD3 exomes AF: 0.0148 AC: 3686 AN: 249656 Hom.: 41 AF XY: 0.0151 AC XY: 2040 AN XY: 135208

Gnomad AFR exome AF: 0.0371

Gnomad AMR exome AF: 0.0138

Gnomad ASJ exome AF: 0.0251

Gnomad EAS exome AF: 0.000164

Gnomad SAS exome AF: 0.0160

Gnomad FIN exome AF: 0.00158

Gnomad NFE exome AF: 0.0150

Gnomad OTH exome AF: 0.0241

GnomAD4 exome AF: 0.0143 AC: 20942 AN: 1459824 Hom.: 223 Cov.: 32 AF XY: 0.0144 AC XY: 10432 AN XY: 726060

Gnomad4 AFR exome AF: 0.0421

Gnomad4 AMR exome AF: 0.0158

Gnomad4 ASJ exome AF: 0.0257

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.0172

Gnomad4 FIN exome AF: 0.00210

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0197

GnomAD4 genome AF: 0.0214 AC: 3262 AN: 152312 Hom.: 48 Cov.: 32 AF XY: 0.0210 AC XY: 1565 AN XY: 74486

Gnomad4 AFR AF: 0.0364

Gnomad4 AMR AF: 0.0285

Gnomad4 ASJ AF: 0.0222

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0170

Gnomad4 FIN AF: 0.00151

Gnomad4 NFE AF: 0.0155

Gnomad4 OTH AF: 0.0232

Alfa AF: 0.0187 Hom.: 45

Bravo AF: 0.0249

Asia WGS AF: 0.00895 AC: 32 AN: 3478

EpiCase AF: 0.0177

EpiControl AF: 0.0177

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

XRCC1-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 27, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	18
Dann	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7

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: rs2307187; hg19: chr19-44079611; COSMIC: COSV53450509; COSMIC: COSV53450509;