rs12727

chr17-1897771-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_002945.5(RPA1):c.*596G>C variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.218 in 153,584 control chromosomes in the GnomAD database, including 3,886 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 0.22 (3869 hom., cov: 32)
  • Exomes 𝑓: 0.17 (17 hom.)
• Consequence: RPA1 NM_002945.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.49

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BA1: GnomAd4 highest subpopulation (SAS) 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.*596G>C		3_prime_UTR_variant	17/17	ENST00000254719.10
RPA1	NM_001355120.2	c.*596G>C		3_prime_UTR_variant	17/17
RPA1	NM_001355121.2	c.*596G>C		3_prime_UTR_variant	16/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RPA1	ENST00000254719.10	c.*596G>C		3_prime_UTR_variant	17/17	1	NM_002945.5	P1
RPA1	ENST00000574049.1	c.*596G>C		3_prime_UTR_variant	8/8	5

Frequencies

GnomAD3 genomes AF: 0.218 AC: 33171 AN: 152016 Hom.: 3854 Cov.: 32

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.193

Gnomad EAS AF: 0.148

Gnomad SAS AF: 0.289

Gnomad FIN AF: 0.174

Gnomad MID AF: 0.210

Gnomad NFE AF: 0.188

Gnomad OTH AF: 0.198

GnomAD4 exome AF: 0.168 AC: 243 AN: 1450 Hom.: 17 Cov.: 0 AF XY: 0.190 AC XY: 143 AN XY: 754

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.168

Gnomad4 EAS exome AF: 0.500

Gnomad4 SAS exome AF: 0.100

Gnomad4 FIN exome AF: 0.177

Gnomad4 NFE exome AF: 0.164

Gnomad4 OTH exome AF: 0.188

GnomAD4 genome AF: 0.218 AC: 33234 AN: 152134 Hom.: 3869 Cov.: 32 AF XY: 0.217 AC XY: 16124 AN XY: 74374

Gnomad4 AFR AF: 0.288

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.193

Gnomad4 EAS AF: 0.148

Gnomad4 SAS AF: 0.289

Gnomad4 FIN AF: 0.174

Gnomad4 NFE AF: 0.188

Gnomad4 OTH AF: 0.207

Alfa AF: 0.206 Hom.: 474

Bravo AF: 0.222

Asia WGS AF: 0.261 AC: 908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
Cadd	Benign	17
Dann	Benign	0.93

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: rs12727; hg19: chr17-1801065;