Genetic Variant XRCC1:c.*35_*50dupACACACACACACACAC (chr19-43543341-C-CGTGTGTGTGTGTGTGT) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

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

The NM_006297.3(XRCC1):c.*35_*50dupACACACACACACACAC variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. It is difficult to determine the true allele frequency of this variant because it is of type INS_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 0.00091 ( 0 hom., cov: 0)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

XRCC1
NM_006297.3 3_prime_UTR

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.110

Publications

2 publications found

Variant links:

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)

XRCC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 127 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_50dupACACACACACACACAC		3_prime_UTR	Exon 17 of 17	NP_006288.2	P18887

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.35_50dupACACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000262887.5	P18887
XRCC1	ENST00000953258.1		c.35_50dupACACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000623317.1
XRCC1	ENST00000865401.1		c.35_50dupACACACACACACACAC	3_prime_UTR	Exon 17 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes

AF:

0.000919

AC:

128

AN:

139220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00292

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000436

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000423

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000244

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.000103

AC:

AN:

905192

Hom.:

Cov.:

AF XY:

0.0000902

AC XY:

AN XY:

465772

show subpopulations

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

African (AFR)

AF:

0.00153

AC:

AN:

20864

American (AMR)

AF:

0.0000797

AC:

AN:

37628

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

20520

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35912

South Asian (SAS)

AF:

0.000199

AC:

AN:

70434

European-Finnish (FIN)

AF:

0.00

AC:

AN:

39768

Middle Eastern (MID)

AF:

0.000256

AC:

AN:

3906

European-Non Finnish (NFE)

AF:

0.0000536

AC:

AN:

634818

Other (OTH)

AF:

0.000194

AC:

AN:

41342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000000392576), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.399

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000912

AC:

127

AN:

139322

Hom.:

Cov.:

AF XY:

0.000862

AC XY:

AN XY:

67316

show subpopulations

African (AFR)

AF:

0.00289

AC:

103

AN:

35696

American (AMR)

AF:

0.000436

AC:

AN:

13772

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3380

East Asian (EAS)

AF:

0.000424

AC:

AN:

4712

South Asian (SAS)

AF:

0.00

AC:

AN:

4304

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8924

Middle Eastern (MID)

AF:

0.00

AC:

AN:

282

European-Non Finnish (NFE)

AF:

0.000244

AC:

AN:

65452

Other (OTH)

AF:

0.00

AC:

AN:

1910

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

133

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.11

Splicing

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

Publications

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19-43543341-CGTGTGTGTGTGTGTGTGTGTGTGTGTGT-CGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over