19-43546043-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006297.3(XRCC1):c.1481+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.403 in 1,612,812 control chromosomes in the GnomAD database, including 136,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10827 hom., cov: 30)
  • Exomes 𝑓: 0.41 (125449 hom.)
• Consequence: XRCC1 NM_006297.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0580

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 19-43546043-C-T is Benign according to our data. Variant chr19-43546043-C-T is described in ClinVar as [Benign]. Clinvar id is 1245878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.425 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC1	NM_006297.3	c.1481+9G>A		intron_variant		ENST00000262887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC1	ENST00000262887.10	c.1481+9G>A		intron_variant		1	NM_006297.3	P1
XRCC1	ENST00000543982.5	c.1388+9G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56207 AN: 151338 Hom.: 10821 Cov.: 30

Gnomad AFR AF: 0.331

Gnomad AMI AF: 0.396

Gnomad AMR AF: 0.272

Gnomad ASJ AF: 0.320

Gnomad EAS AF: 0.110

Gnomad SAS AF: 0.353

Gnomad FIN AF: 0.458

Gnomad MID AF: 0.287

Gnomad NFE AF: 0.429

Gnomad OTH AF: 0.359

GnomAD3 exomes AF: 0.355 AC: 89171 AN: 250958 Hom.: 17611 AF XY: 0.365 AC XY: 49453 AN XY: 135608

Gnomad AFR exome AF: 0.335

Gnomad AMR exome AF: 0.193

Gnomad ASJ exome AF: 0.325

Gnomad EAS exome AF: 0.109

Gnomad SAS exome AF: 0.376

Gnomad FIN exome AF: 0.451

Gnomad NFE exome AF: 0.426

Gnomad OTH exome AF: 0.366

GnomAD4 exome AF: 0.406 AC: 593905 AN: 1461356 Hom.: 125449 Cov.: 43 AF XY: 0.407 AC XY: 296148 AN XY: 726992

Gnomad4 AFR exome AF: 0.333

Gnomad4 AMR exome AF: 0.201

Gnomad4 ASJ exome AF: 0.321

Gnomad4 EAS exome AF: 0.104

Gnomad4 SAS exome AF: 0.374

Gnomad4 FIN exome AF: 0.455

Gnomad4 NFE exome AF: 0.432

Gnomad4 OTH exome AF: 0.383

GnomAD4 genome AF: 0.371 AC: 56255 AN: 151456 Hom.: 10827 Cov.: 30 AF XY: 0.369 AC XY: 27311 AN XY: 73990

Gnomad4 AFR AF: 0.331

Gnomad4 AMR AF: 0.271

Gnomad4 ASJ AF: 0.320

Gnomad4 EAS AF: 0.110

Gnomad4 SAS AF: 0.354

Gnomad4 FIN AF: 0.458

Gnomad4 NFE AF: 0.429

Gnomad4 OTH AF: 0.358

Alfa AF: 0.400 Hom.: 8668

Bravo AF: 0.349

Asia WGS AF: 0.249 AC: 869 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.421

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

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 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
Cadd	Benign	7.2
Dann	Benign	0.79
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs25479; hg19: chr19-44050195; COSMIC: COSV53447239;