19-43570445-T-G

Variant names:

• chr19-43570445-T-G
• rs2854509
• NM_006297.3:c.144+4465A>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006297.3(XRCC1):​c.144+4465A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.799 in 152,154 control chromosomes in the GnomAD database, including 48,718 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 0.80 (48718 hom., cov: 32)
• Consequence: XRCC1 NM_006297.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.384
• Publications: 21 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)

ENSG00000268361 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.863 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.144+4465A>C		intron	N/A	NP_006288.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	XRCC1	ENST00000262887.10	TSL:1 MANE Select	c.144+4465A>C		intron	N/A	ENSP00000262887.5
	ENSG00000268361	ENST00000594374.1	TSL:3	c.169-9425A>C		intron	N/A	ENSP00000472698.1
	XRCC1	ENST00000543982.5	TSL:2	c.51+4963A>C		intron	N/A	ENSP00000443671.1

Frequencies

GnomAD3 genomes AF: 0.800 AC: 121554 AN: 152036 Hom.: 48692 Cov.: 32

Gnomad AFR AF: 0.810

Gnomad AMI AF: 0.839

Gnomad AMR AF: 0.867

Gnomad ASJ AF: 0.814

Gnomad EAS AF: 0.885

Gnomad SAS AF: 0.775

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.858

Gnomad NFE AF: 0.781

Gnomad OTH AF: 0.807

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.799 AC: 121635 AN: 152154 Hom.: 48718 Cov.: 32 AF XY: 0.800 AC XY: 59458 AN XY: 74368

African (AFR) AF: 0.810 AC: 33608 AN: 41502

American (AMR) AF: 0.867 AC: 13249 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.814 AC: 2827 AN: 3472

East Asian (EAS) AF: 0.884 AC: 4581 AN: 5180

South Asian (SAS) AF: 0.775 AC: 3740 AN: 4824

European-Finnish (FIN) AF: 0.736 AC: 7785 AN: 10578

Middle Eastern (MID) AF: 0.854 AC: 251 AN: 294

European-Non Finnish (NFE) AF: 0.781 AC: 53129 AN: 68004

Other (OTH) AF: 0.806 AC: 1700 AN: 2110

Alfa AF: 0.797 Hom.: 81135

Bravo AF: 0.814

Asia WGS AF: 0.806 AC: 2801 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.38
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: rs2854509; hg19: chr19-44074597;