rs25479

Variant names:

• chr19-43546043-C-T
• rs25479
• NM_006297.3:c.1481+9G>A

Variant summary

Our verdict is Benign. The variant received -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:3
• Conservation: PhyloP100: 0.0580
• Publications: 15 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006297.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	NM_006297.3	MANE Select	c.1481+9G>A		intron	N/A	NP_006288.2	P18887

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.1481+9G>A		intron	N/A	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.1493+9G>A		intron	N/A	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.1478+9G>A		intron	N/A	ENSP00000535460.1

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

GnomAD2 exomes AF: 0.355 AC: 89171 AN: 250958 AF XY: 0.365

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 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

African (AFR) AF: 0.333 AC: 11157 AN: 33472

American (AMR) AF: 0.201 AC: 8979 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 8377 AN: 26106

East Asian (EAS) AF: 0.104 AC: 4115 AN: 39696

South Asian (SAS) AF: 0.374 AC: 32263 AN: 86242

European-Finnish (FIN) AF: 0.455 AC: 24296 AN: 53398

Middle Eastern (MID) AF: 0.295 AC: 1701 AN: 5762

European-Non Finnish (NFE) AF: 0.432 AC: 479867 AN: 1111618

Other (OTH) AF: 0.383 AC: 23150 AN: 60370

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

African (AFR) AF: 0.331 AC: 13677 AN: 41266

American (AMR) AF: 0.271 AC: 4142 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.320 AC: 1107 AN: 3464

East Asian (EAS) AF: 0.110 AC: 566 AN: 5146

South Asian (SAS) AF: 0.354 AC: 1689 AN: 4772

European-Finnish (FIN) AF: 0.458 AC: 4825 AN: 10530

Middle Eastern (MID) AF: 0.295 AC: 86 AN: 292

European-Non Finnish (NFE) AF: 0.429 AC: 29051 AN: 67710

Other (OTH) AF: 0.358 AC: 752 AN: 2098

Alfa AF: 0.398 Hom.: 9628

Bravo AF: 0.349

Asia WGS AF: 0.249 AC: 869 AN: 3478

EpiCase AF: 0.416

EpiControl AF: 0.421

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Spinocerebellar ataxia, autosomal recessive 26 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	7.2
DANN	Benign	0.79
PhyloP100		0.058
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs25479; hg19: chr19-44050195; COSMIC: COSV53447239;