19-43543398-T-C

Variant names:

• chr19-43543398-T-C
• rs3547
• NM_006297.3:c.1896A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_006297.3(XRCC1):​c.1896A>G​(p.Gln632Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.596 in 1,587,640 control chromosomes in the GnomAD database, including 288,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.63 (29553 hom., cov: 24)
  • Exomes 𝑓: 0.59 (258642 hom.)
• Consequence: XRCC1 NM_006297.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.339
• Publications: 54 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 19-43543398-T-C is Benign according to our data. Variant chr19-43543398-T-C is described in ClinVar as Benign. ClinVar VariationId is 1684239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.339 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.864 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	NM_006297.3	MANE Select	c.1896A>G	p.Gln632Gln	synonymous	Exon 17 of 17	NP_006288.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.1896A>G	p.Gln632Gln	synonymous	Exon 17 of 17	ENSP00000262887.5
	XRCC1	ENST00000543982.5	TSL:2	c.1803A>G	p.Gln601Gln	synonymous	Exon 16 of 16	ENSP00000443671.1

Frequencies

GnomAD3 genomes AF: 0.625 AC: 93056 AN: 148772 Hom.: 29535 Cov.: 24

Gnomad AFR AF: 0.663

Gnomad AMI AF: 0.602

Gnomad AMR AF: 0.729

Gnomad ASJ AF: 0.680

Gnomad EAS AF: 0.886

Gnomad SAS AF: 0.643

Gnomad FIN AF: 0.540

Gnomad MID AF: 0.709

Gnomad NFE AF: 0.570

Gnomad OTH AF: 0.639

GnomAD2 exomes AF: 0.644 AC: 159895 AN: 248392 AF XY: 0.634

Gnomad AFR exome AF: 0.663

Gnomad AMR exome AF: 0.805

Gnomad ASJ exome AF: 0.674

Gnomad EAS exome AF: 0.891

Gnomad FIN exome AF: 0.545

Gnomad NFE exome AF: 0.573

Gnomad OTH exome AF: 0.634

GnomAD4 exome AF: 0.593 AC: 853299 AN: 1438750 Hom.: 258642 Cov.: 37 AF XY: 0.592 AC XY: 424311 AN XY: 716604

African (AFR) AF: 0.664 AC: 21967 AN: 33082

American (AMR) AF: 0.799 AC: 35646 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17593 AN: 25920

East Asian (EAS) AF: 0.896 AC: 35499 AN: 39600

South Asian (SAS) AF: 0.625 AC: 53656 AN: 85794

European-Finnish (FIN) AF: 0.544 AC: 27945 AN: 51324

Middle Eastern (MID) AF: 0.703 AC: 3979 AN: 5660

European-Non Finnish (NFE) AF: 0.567 AC: 620258 AN: 1093048

Other (OTH) AF: 0.616 AC: 36756 AN: 59684

GnomAD4 genome AF: 0.625 AC: 93127 AN: 148890 Hom.: 29553 Cov.: 24 AF XY: 0.628 AC XY: 45527 AN XY: 72492

African (AFR) AF: 0.663 AC: 26459 AN: 39908

American (AMR) AF: 0.729 AC: 10859 AN: 14892

Ashkenazi Jewish (ASJ) AF: 0.680 AC: 2354 AN: 3464

East Asian (EAS) AF: 0.886 AC: 4417 AN: 4988

South Asian (SAS) AF: 0.642 AC: 3024 AN: 4710

European-Finnish (FIN) AF: 0.540 AC: 5440 AN: 10080

Middle Eastern (MID) AF: 0.701 AC: 206 AN: 294

European-Non Finnish (NFE) AF: 0.570 AC: 38507 AN: 67592

Other (OTH) AF: 0.640 AC: 1313 AN: 2052

Alfa AF: 0.598 Hom.: 6036

Bravo AF: 0.649

Asia WGS AF: 0.748 AC: 2593 AN: 3474

EpiCase AF: 0.584

EpiControl AF: 0.578

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spinocerebellar ataxia, autosomal recessive 26 Benign:1

Dec 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	4.0
DANN	Benign	0.41
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=81/19	polymorphism

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: rs3547; hg19: chr19-44047550; COSMIC: COSV53447140;