Genetic Variant NM_006297.3:c.1621+109C>A (chr19-43545709-G-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_006297.3(XRCC1):c.1621+109C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0707 in 1,435,060 control chromosomes in the GnomAD database, including 5,056 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.073 ( 585 hom., cov: 32)

Exomes 𝑓: 0.071 ( 4471 hom. )

Consequence

XRCC1
NM_006297.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00100

Publications

8 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: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
XRCC1	NM_006297.3 link	c.1621+109C>A		intron_variant	Intron 14 of 16	ENST00000262887.10	NP_006288.2	P18887B2RCY5Q59HH7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
XRCC1	ENST00000262887.10 link	c.1621+109C>A		intron_variant	Intron 14 of 16	1	NM_006297.3	ENSP00000262887.5		P18887
XRCC1	ENST00000543982.5 link	c.1528+109C>A		intron_variant	Intron 13 of 15	2		ENSP00000443671.1		F5H8D7

Frequencies

GnomAD3 genomes

AF:

0.0727

AC:

11058

AN:

152084

Hom.:

585

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0642

Gnomad AMI

AF:

0.0263

Gnomad AMR

AF:

0.101

Gnomad ASJ

AF:

0.0591

Gnomad EAS

AF:

0.265

Gnomad SAS

AF:

0.103

Gnomad FIN

AF:

0.0369

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0613

Gnomad OTH

AF:

0.0857

GnomAD4 exome

AF:

0.0705

AC:

90460

AN:

1282858

Hom.:

4471

AF XY:

0.0710

AC XY:

45118

AN XY:

635320

show subpopulations

African (AFR)

AF:

0.0656

AC:

1919

AN:

29236

American (AMR)

AF:

0.139

AC:

4740

AN:

33992

Ashkenazi Jewish (ASJ)

AF:

0.0649

AC:

1309

AN:

20164

East Asian (EAS)

AF:

0.279

AC:

10740

AN:

38482

South Asian (SAS)

AF:

0.0926

AC:

6589

AN:

71180

European-Finnish (FIN)

AF:

0.0375

AC:

1738

AN:

46402

Middle Eastern (MID)

AF:

0.0767

AC:

397

AN:

5176

European-Non Finnish (NFE)

AF:

0.0597

AC:

58775

AN:

984476

Other (OTH)

AF:

0.0791

AC:

4253

AN:

53750

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

3998

7996

11994

15992

19990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2372

4744

7116

9488

11860

<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:

0.0727

AC:

11060

AN:

152202

Hom.:

585

Cov.:

AF XY:

0.0732

AC XY:

5448

AN XY:

74416

show subpopulations

African (AFR)

AF:

0.0641

AC:

2663

AN:

41532

American (AMR)

AF:

0.101

AC:

1548

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0591

AC:

205

AN:

3470

East Asian (EAS)

AF:

0.265

AC:

1366

AN:

5162

South Asian (SAS)

AF:

0.102

AC:

492

AN:

4824

European-Finnish (FIN)

AF:

0.0369

AC:

392

AN:

10610

Middle Eastern (MID)

AF:

0.0816

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0613

AC:

4165

AN:

67992

Other (OTH)

AF:

0.0858

AC:

181

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

515

1029

1544

2058

2573

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

126

252

378

504

630

<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:

0.0630

Hom.:

Bravo

AF:

0.0794

Asia WGS

AF:

0.184

AC:

640

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

2.8

(source)

DANN

Benign

0.87

PhyloP100

-0.0010

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over