19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr19-43543341-C-CGTGT
• rs45592142
• NM_006297.3:c.*47_*50dupACAC

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

The NM_006297.3(XRCC1):​c.*47_*50dupACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.089 (610 hom., cov: 0)
  • Exomes 𝑓: 0.053 (104 hom.)
• Consequence: XRCC1 NM_006297.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.110
• Publications: 2 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 -8 ACMG points.

• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.153 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.*47_*50dupACAC		3_prime_UTR	Exon 17 of 17	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.*47_*50dupACAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*47_*50dupACAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*47_*50dupACAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.0887 AC: 12339 AN: 139064 Hom.: 607 Cov.: 0

Gnomad AFR AF: 0.0539

Gnomad AMI AF: 0.0528

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.0711

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.100

Gnomad MID AF: 0.0728

Gnomad NFE AF: 0.0952

Gnomad OTH AF: 0.0971

GnomAD4 exome AF: 0.0530 AC: 47579 AN: 898048 Hom.: 104 Cov.: 0 AF XY: 0.0529 AC XY: 24461 AN XY: 462066

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0340 AC: 705 AN: 20764

American (AMR) AF: 0.135 AC: 4981 AN: 37028

Ashkenazi Jewish (ASJ) AF: 0.0488 AC: 994 AN: 20356

East Asian (EAS) AF: 0.0876 AC: 3090 AN: 35294

South Asian (SAS) AF: 0.0295 AC: 2067 AN: 70162

European-Finnish (FIN) AF: 0.0714 AC: 2804 AN: 39264

Middle Eastern (MID) AF: 0.0513 AC: 199 AN: 3876

European-Non Finnish (NFE) AF: 0.0483 AC: 30416 AN: 630312

Other (OTH) AF: 0.0567 AC: 2323 AN: 40992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0887 AC: 12350 AN: 139166 Hom.: 610 Cov.: 0 AF XY: 0.0893 AC XY: 6002 AN XY: 67226

African (AFR) AF: 0.0540 AC: 1924 AN: 35662

American (AMR) AF: 0.159 AC: 2179 AN: 13734

Ashkenazi Jewish (ASJ) AF: 0.0711 AC: 240 AN: 3376

East Asian (EAS) AF: 0.105 AC: 494 AN: 4706

South Asian (SAS) AF: 0.0335 AC: 144 AN: 4300

European-Finnish (FIN) AF: 0.100 AC: 890 AN: 8904

Middle Eastern (MID) AF: 0.0780 AC: 22 AN: 282

European-Non Finnish (NFE) AF: 0.0952 AC: 6225 AN: 65402

Other (OTH) AF: 0.0969 AC: 185 AN: 1910

Alfa AF: 0.0599 Hom.: 133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.11
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs45592142; hg19: chr19-44047493; COSMIC: COSV53451299;