rs2270412

chr17-1888880-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002945.5(RPA1):c.1551+29G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.204 in 1,599,184 control chromosomes in the GnomAD database, including 35,215 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (2741 hom., cov: 32)
  • Exomes 𝑓: 0.21 (32474 hom.)
• Consequence: RPA1 NM_002945.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.988

Genes affected

RPA1 (HGNC:10289): (replication protein A1) This gene encodes the largest subunit of the heterotrimeric Replication Protein A (RPA) complex, which binds to single-stranded DNA (ssDNA), forming a nucleoprotein complex that plays an important role in DNA metabolism, being involved in DNA replication, repair, recombination, telomere maintenance, and co-ordinating the cellular response to DNA damage through activation of the ataxia telangiectasia and Rad3-related protein (ATR) kinase. The nucleoprotein complex protects the single-stranded DNA from nucleases, prevents formation of secondary structures that would interfere with repair, and co-ordinates the recruitment and departure of different genome maintenance factors. This subunit contains four oligonucleotide/oligosaccharide-binding (OB) domains, though the majority of ssDNA binding occurs in two of these domains. The heterotrimeric complex has two different modes of ssDNA binding, a low-affinity and high-affinity mode, determined by which ssDNA binding domains are utilized. The different binding modes differ in the length of DNA bound and in the proteins with which it interacts, thereby playing a role in regulating different genomic maintenance pathways. [provided by RefSeq, Sep 2017]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 17-1888880-G-A is Benign according to our data. Variant chr17-1888880-G-A is described in ClinVar as [Benign]. Clinvar id is 2688163.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RPA1	NM_002945.5	c.1551+29G>A		intron_variant		ENST00000254719.10
RPA1	NM_001355120.2	c.1512+29G>A		intron_variant
RPA1	NM_001355121.2	c.1375-2953G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA1	ENST00000254719.10	c.1551+29G>A		intron_variant		1	NM_002945.5	P1
RPA1	ENST00000574049.1	c.643-2953G>A		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25691 AN: 152084 Hom.: 2746 Cov.: 32

Gnomad AFR AF: 0.0388

Gnomad AMI AF: 0.205

Gnomad AMR AF: 0.211

Gnomad ASJ AF: 0.204

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.269

Gnomad MID AF: 0.231

Gnomad NFE AF: 0.209

Gnomad OTH AF: 0.190

GnomAD3 exomes AF: 0.215 AC: 52365 AN: 243968 Hom.: 5927 AF XY: 0.216 AC XY: 28442 AN XY: 131666

Gnomad AFR exome AF: 0.0345

Gnomad AMR exome AF: 0.233

Gnomad ASJ exome AF: 0.226

Gnomad EAS exome AF: 0.299

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.267

Gnomad NFE exome AF: 0.217

Gnomad OTH exome AF: 0.219

GnomAD4 exome AF: 0.208 AC: 300895 AN: 1446982 Hom.: 32474 Cov.: 31 AF XY: 0.209 AC XY: 149956 AN XY: 717836

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.216

Gnomad4 EAS exome AF: 0.316

Gnomad4 SAS exome AF: 0.191

Gnomad4 FIN exome AF: 0.264

Gnomad4 NFE exome AF: 0.207

Gnomad4 OTH exome AF: 0.197

GnomAD4 genome AF: 0.169 AC: 25690 AN: 152202 Hom.: 2741 Cov.: 32 AF XY: 0.173 AC XY: 12845 AN XY: 74408

Gnomad4 AFR AF: 0.0387

Gnomad4 AMR AF: 0.211

Gnomad4 ASJ AF: 0.204

Gnomad4 EAS AF: 0.297

Gnomad4 SAS AF: 0.188

Gnomad4 FIN AF: 0.269

Gnomad4 NFE AF: 0.209

Gnomad4 OTH AF: 0.188

Alfa AF: 0.209 Hom.: 4918

Bravo AF: 0.162

Asia WGS AF: 0.197 AC: 685 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Jan 24, 2024

This variant is classified as Benign based on local population frequency. This variant was detected in 43% of patients studied by a panel of primary immunodeficiencies. Number of patients: 41. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	0.34
Dann	Benign	0.68
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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

LitVar

Other links and lift over

dbSNP: rs2270412; hg19: chr17-1792174; COSMIC: COSV54613460; COSMIC: COSV54613460;