chr19-43543341-CGTGTGTGTGTGTGTGT-C

Variant names:

• chr19-43543341-CGTGTGTGTGTGTGTGT-C
• rs45592142
• NM_006297.3:c.*35_*50delACACACACACACACAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_006297.3(XRCC1):​c.*35_*50delACACACACACACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00125 in 1,043,118 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0014 (0 hom.)
• Consequence: XRCC1 NM_006297.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.19
• 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: Likely_benign. The variant received -4 ACMG points.

• BS2: High AC in GnomAd4 at 49 AD,Unknown gene.

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.*35_*50delACACACACACACACAC		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.*35_*50delACACACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.*35_*50delACACACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.*35_*50delACACACACACACACAC		3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes AF: 0.000359 AC: 50 AN: 139214 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000145

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000232

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00211

GnomAD4 exome AF: 0.00139 AC: 1260 AN: 903802 Hom.: 0 AF XY: 0.00142 AC XY: 660 AN XY: 464980

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

African (AFR) AF: 0.00259 AC: 54 AN: 20878

American (AMR) AF: 0.00364 AC: 136 AN: 37406

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 25 AN: 20480

East Asian (EAS) AF: 0.00193 AC: 69 AN: 35780

South Asian (SAS) AF: 0.00247 AC: 173 AN: 70164

European-Finnish (FIN) AF: 0.00159 AC: 63 AN: 39656

Middle Eastern (MID) AF: 0.00335 AC: 13 AN: 3878

European-Non Finnish (NFE) AF: 0.00106 AC: 670 AN: 634290

Other (OTH) AF: 0.00138 AC: 57 AN: 41270

⚠️ 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: 0.000352 AC: 49 AN: 139316 Hom.: 0 Cov.: 0 AF XY: 0.000386 AC XY: 26 AN XY: 67314

African (AFR) AF: 0.00120 AC: 43 AN: 35698

American (AMR) AF: 0.000145 AC: 2 AN: 13772

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3380

East Asian (EAS) AF: 0.00 AC: 0 AN: 4710

South Asian (SAS) AF: 0.00 AC: 0 AN: 4304

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8918

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 282

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65452

Other (OTH) AF: 0.00209 AC: 4 AN: 1910

Alfa AF: 0.00 Hom.: 133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism

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;