19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr19-43543341-CGT-C
• rs45592142
• NM_006297.3:c.*49_*50delAC

Variant summary

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

The NM_006297.3(XRCC1):​c.*49_*50delAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.147 in 1,020,224 control chromosomes in the GnomAD database, including 1,235 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.10 (835 hom., cov: 0)
  • Exomes 𝑓: 0.15 (400 hom.)
• Consequence: XRCC1 NM_006297.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.612
• 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 (EAS) allele frequency at 95% confidence interval = 0.267 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.*49_*50delAC		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.*49_*50delAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*49_*50delAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*49_*50delAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 14034 AN: 138854 Hom.: 834 Cov.: 0

Gnomad AFR AF: 0.0707

Gnomad AMI AF: 0.0449

Gnomad AMR AF: 0.134

Gnomad ASJ AF: 0.151

Gnomad EAS AF: 0.279

Gnomad SAS AF: 0.113

Gnomad FIN AF: 0.0699

Gnomad MID AF: 0.116

Gnomad NFE AF: 0.0982

Gnomad OTH AF: 0.134

GnomAD4 exome AF: 0.154 AC: 136006 AN: 881272 Hom.: 400 AF XY: 0.157 AC XY: 71282 AN XY: 453082

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

African (AFR) AF: 0.125 AC: 2542 AN: 20324

American (AMR) AF: 0.197 AC: 7245 AN: 36712

Ashkenazi Jewish (ASJ) AF: 0.209 AC: 4137 AN: 19762

East Asian (EAS) AF: 0.292 AC: 10181 AN: 34920

South Asian (SAS) AF: 0.169 AC: 11497 AN: 67940

European-Finnish (FIN) AF: 0.151 AC: 5751 AN: 38180

Middle Eastern (MID) AF: 0.145 AC: 553 AN: 3802

European-Non Finnish (NFE) AF: 0.141 AC: 87395 AN: 619420

Other (OTH) AF: 0.167 AC: 6705 AN: 40212

⚠️ 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: 0.101 AC: 14053 AN: 138952 Hom.: 835 Cov.: 0 AF XY: 0.101 AC XY: 6759 AN XY: 67120

African (AFR) AF: 0.0711 AC: 2535 AN: 35652

American (AMR) AF: 0.135 AC: 1849 AN: 13736

Ashkenazi Jewish (ASJ) AF: 0.151 AC: 511 AN: 3378

East Asian (EAS) AF: 0.279 AC: 1314 AN: 4706

South Asian (SAS) AF: 0.113 AC: 487 AN: 4298

European-Finnish (FIN) AF: 0.0699 AC: 616 AN: 8814

Middle Eastern (MID) AF: 0.113 AC: 32 AN: 282

European-Non Finnish (NFE) AF: 0.0982 AC: 6413 AN: 65298

Other (OTH) AF: 0.135 AC: 256 AN: 1898

Alfa AF: 0.129 Hom.: 133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.61
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs45592142; hg19: chr19-44047493; COSMIC: COSV106055629;