rs2307191

Positions:

• chr19-43553616-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006297.3(XRCC1):​c.482C>T​(p.Pro161Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000845 in 1,595,824 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Synonymous variant affecting the same amino acid position (i.e. P161P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (3 hom., cov: 31)
  • Exomes 𝑓: 0.00046 (5 hom.)
• Consequence: XRCC1 NM_006297.3 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.98

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0058294237).
• BP6: Variant 19-43553616-G-A is Benign according to our data. Variant chr19-43553616-G-A is described in ClinVar as [Benign]. Clinvar id is 784399.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000456 (658/1443942) while in subpopulation AFR AF= 0.0169 (558/33112). AF 95% confidence interval is 0.0157. There are 5 homozygotes in gnomad4_exome. There are 276 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
XRCC1	NM_006297.3	c.482C>T	p.Pro161Leu	missense_variant	5/17	ENST00000262887.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
XRCC1	ENST00000262887.10	c.482C>T	p.Pro161Leu	missense_variant	5/17	1	NM_006297.3	P1
	ENST00000597119.1	n.83+89G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00452 AC: 686 AN: 151764 Hom.: 3 Cov.: 31

Gnomad AFR AF: 0.0157

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.00125 AC: 306 AN: 245186 Hom.: 2 AF XY: 0.000839 AC XY: 111 AN XY: 132304

Gnomad AFR exome AF: 0.0168

Gnomad AMR exome AF: 0.000678

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000542

Gnomad OTH exome AF: 0.000844

GnomAD4 exome AF: 0.000456 AC: 658 AN: 1443942 Hom.: 5 Cov.: 33 AF XY: 0.000386 AC XY: 276 AN XY: 715004

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000796

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.0000351

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000137

Gnomad4 OTH exome AF: 0.000740

GnomAD4 genome AF: 0.00455 AC: 691 AN: 151882 Hom.: 3 Cov.: 31 AF XY: 0.00401 AC XY: 298 AN XY: 74234

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000736

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.000855 Hom.: 2

Bravo AF: 0.00532

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0163 AC: 72

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00152 AC: 184

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.62
CADD	Uncertain	25
DANN	Uncertain	0.99
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.21
FATHMM_MKL	Benign	0.65	D
MetaRNN	Benign	0.0058	T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.9	D;D;.;.
REVEL	Benign	0.069
Sift	Uncertain	0.016	D;D;.;.
Sift4G	Uncertain	0.047	D;D;D;.
Polyphen		0.35	.;B;.;.
Vest4		0.14
MVP		0.25
MPC		0.26
ClinPred		0.040	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
gMVP		0.33

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs2307191; hg19: chr19-44057768;