19-43545889-C-A

Variant names:

• chr19-43545889-C-A
• rs747431224
• NM_006297.3:c.1550G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006297.3(XRCC1):​c.1550G>T​(p.Gly517Val) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G517A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20467743).

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.1550G>T	p.Gly517Val	missense	Exon 14 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.1550G>T	p.Gly517Val	missense	Exon 14 of 17	ENSP00000262887.5	P18887
	XRCC1	ENST00000953258.1		c.1562G>T	p.Gly521Val	missense	Exon 14 of 17	ENSP00000623317.1
	XRCC1	ENST00000865401.1		c.1547G>T	p.Gly516Val	missense	Exon 14 of 17	ENSP00000535460.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.34
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.029	T
Eigen	Benign	-0.091
Eigen_PC	Benign	-0.011
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.0	T
PhyloP100		4.4
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.11
Sift	Benign	0.046	D
Sift4G	Benign	0.11	T
Polyphen		0.25	B
Vest4		0.45
MutPred		0.21		Loss of relative solvent accessibility (P = 0.107)
MVP		0.23
MPC		0.39
ClinPred		0.94	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.48
Mutation Taster		=53/47	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: rs747431224; hg19: chr19-44050041;